Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[C:22]1(=[O:32])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24](=[O:31])[O:23]1.S(=O)(=O)(O)O>O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]([C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=2[C:22]([OH:32])=[O:23])=[O:31])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Nc1ccc(C(=O)C2=C(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.2 g magnesium turnings (83.5 mmol) in 15 ml tetrahydrofuran were added 0.1 mL 1,2-dibromethane to start the Grignard reaction followed by slow addition of 13.0 g 2-(4-bromphenyl)-1,1,1,3,3,3-hexamethyldisilazane (41 mmol) in 70 mL tetrahydrofuran over a period of 20 minutes at room temperature with subsequent stirring for further 30 minutes. The resulting mixture was added dropwise at −78° C. to a solution of 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (5.6 g) in 70 mL tetrahydrofuran. The reaction mixture was slowly warmed to room temperature. Sulfuric acid (2 mL, 1 M) was added and the solvent was removed under reduced pressure. The residue was added carefully to 20 mL of 0.5 M sulfuric acid solution and the desired product started to precipitate and was extracted with ethyl acetate. Acidification of the water phase and extraction with ethyl acetate was continued until pH˜4-5 (at least three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and the solvent was subsequently evaporated under reduced pressure. Purification of the raw material by column chromatography with ethyl acetate/hexane 1:1 and subsequently 100% ethyl acetate resulted in the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[CH3:16][C:17]1O[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[N:19][N:18]=1>O1CCCC1>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[C:17]([CH3:16])=[N:18][N:19]=[C:20]2[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1nnc(-c2ccc(C#N)cc2)o1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(-c2ccc(C#N)cc2)n1-c1ccc(Cl)cc1

Procedure:
Trifluoroacetic acid (600 μl, 8.1 mmol) was added to a suspension of 4-chloroaniline (2.1 g, 16.2 mmol) and 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzonitrile (Journal für Praktische Chemie, 1994; 336(8); 678-85) (3.0 g, 16.2 mmol) in tetrahydrofuran (50 mL) and the reaction was heated at reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 mL) and 20% aqueous 0.88 ammonia (120 mL), and then the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with ether and a minimum volume of ethyl acetate to afford the title compound as a white crystalline solid, 2.82 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Br:13]Br.C(=O)([O-])[O-].[K+].[K+].O>CO>[Br:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCc1ccccc1C(=O)OC
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1ccc(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The above methyl 2-ethylbenzoate was mixed with molecular sieve 13× (powder, 70 g), and while stirring the mixture, bromine (5.2 ml) was added dropwise thereto at 80° C. The mixture was further stirred at the same temperature for 1.5 hours. The mixture was cooled to room temperature, and added thereto were potassium carbonate (7.4 g), water (70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours. Insoluble materials were filtered off, and suspended in a mixed solution of methanol (500 ml)-water (500 ml), and the mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the filtrate was combined with the previously obtained filtrate, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure, to give methyl 5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[O:23])[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(Cl)cc1C=O
Temperature: -78 °C
Yield: 56.1 %

Procedure:
To a chilled (−78° C.), stirred solution of the amide (Step 1) (5.0 g, 0.024 mole) in tetrahydrofuran (100 mL) was added t-butyl lithium (1.7M in pentane, 32.4 mL, 0.055 mole) dropwise. Dimethylformamide (2.3 mL, 0.03 mole) was added dropwise at −78° C. over 3 hours and the mixture allowed to warm room temperature. The reaction was quenched with ice water (200 mL) and extracted with ethyl acetate. The resulting organic phase was dried over MgSO4 and was concentrated in vacuo to a volume of 20 mL. A white solid precipitated which was collected by filtration yielding the formylated product (3.24 g, 56%): mp 168.7–170.8° C. 1H NMR (CDCl3/300 MHz) 10.60 (br s, 1H), 9.88 (s, 1H), 8.57 (s, 1H), 8.00 (s, 1H), 1.28 (s, 9H). Anal. Calc'd for C11H13N2O2Cl: C, 54.89; H, 5.44; N, 11.64 Found: C, 54.87; H, 5.42; N, 11.40.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[C:21]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)(=[O:23])[CH3:22].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CN(C)C=O>[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH:1][C:2]2[N:11]=[CH:10][C:9]3[CH2:8][CH2:7][C:6]4[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=4[C:4]=3[N:3]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Reactant: CC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(C)=O)CC3)nc1-2
Reaction time: 18 h
Yield: 70 %

Procedure:
To a suspension of 5.187 g (19 mmol) of ethyl 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in dry dimethylformamide (120 mL), were added 1-acetyl-4-piperidone (4.7 mL, 38 mmol), CF3COOH (10 mL, 128 mmol) and NaBH(OAc)3 (8.862 g, 42 mmol). After 18 hours, NaOH 0.33N (800 mL, 264 mmol) was added dropwise to the mixture. The precipitate was filtered, washed with water and dried in oven to dryness to give 5.3 g (70% yield) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][C:18]=1[F:25]>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][C:18]=1[F:25]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1cc(CBr)ccc1Br
Product: N#Cc1ccc(N(Cc2ccc(Br)c(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 4-bromo-3-fluorobenzyl bromide
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH:9]=[C:8]2[CH3:15])[O:4][N:3]=1.[H][H]>C(O)C.[Pt]=O>[CH3:15][C:8]1[CH:7]([C:5](=[O:4])[CH:6]=[C:2]([NH2:3])[CH3:1])[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]=1
Reactant: CC1=CCCC(C)(C)C1c1cc(C)no1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(N)=CC(=O)C1C(C)=CCCC1(C)C
Yield: 90 %

Procedure:
4.10 g (0.020 mole) of 3-methyl-5-[2,6,6-trimethylcyclohex-2-en-1-yl]-isoxazole were dissolved in 5 ml of anhydrous ethanol and the solution was added to 0.173 g of a mixture of 83.6 % of platinum oxide in 30 ml of ethanol, the said mixture having previously been subjected to a hydrogenation. The solution was then subjected to a hydrogenation at room temperature and at atmospheric pressure and, after absorption of one equivalent of hydrogen, filtered through a "Celite" carrier. After having been concentrated under reduced pressure the residual solution was subjected to chromatography on a magnesium silicate column by elution with a mixture of chloroform/hexane (25/75) to yield 3.73 g (yield: 90 %) of 2,6,6-trimethyl-1-[3-amino-but- 2-en-1-oyl]-cyclohex-2-ene.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:23]([O:30][C:31]([NH:33][C:34]1([C:37]([OH:39])=O)[CH2:36][CH2:35]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:40]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH2:40]([N:47]([C:37]([C:34]1([NH:33][C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:32])[CH2:35][CH2:36]1)=[O:39])[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: CCOC(=O)CNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.0 g, 110 mmol) and 1-hydroxybenzotriazole (2.70 g, 20 mmol) were added to a dichloromethane (235 ml) solution of 1-{[(benzyloxy)carbonyl]amino}cyclopropanecarboxylic acid (23.5 g, 100 mmol) and ethyl N-benzylglycinate (19.3 g, 100 mmol) under ice cooling and the resulting mixture was stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure and then the residue was diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=2:1 (v/v)] to give the title compound (35.7 g, 87%) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)O1>>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1
Reactant: CC1(C)OB(c2ccc(N3CCS(=O)(=O)CC3)cc2)OC1(C)C
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: NC(=O)c1cc(-c2ccc(N3CCS(=O)(=O)CC3)cc2)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (300 mg, 1.20 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiomorpholine 1,1-dioxide (403 mg, 1.20 mmol) according to the general procedure described in Intermediate 10 Step 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH:12]([CH2:18][NH2:19])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:41]([C:31]1[CH:30]=[C:29]([NH:28][C:27]([NH:19][CH2:18][CH:12]2[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:26])[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=1)[CH3:42]
Reactant: CC1(C)CCN(CCc2ccc(F)cc2)CC1CN
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)NCC2CN(CCc3ccc(F)cc3)CCC2(C)C)cc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)ethyl]-4,4-dimethyl-piperidin-3-ylmethylamine (53 mg, 199 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (50 mg, 199 μmol) in N,N-dimethylformamide (1.0 mL) was treated with triethylamine (55 μL, 398 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, providing an amorphous solid (50 mg, 50%). 1H NMR (300 MHz, CDCl3) δ8.45 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.09 (m, 2H), 7.07 (s, 1H), 6.91 (t, J=9 Hz, 2H), 6.23 (m, 1H), 4.13 (s, 3H), 3.38 (m, 1H), 3.10 (m, 2H), 2.85 (m, 3H), 2.74 (m, 2H), 2.62 (q, J=7 Hz, 2H), 2.45 (m, 1H), 2.32 (m, 1H), 1.8-1.6 (m, 2H), 1.46 (m, 1H), 1.21 (t, J=7 Hz, 3H), 1.02 (s, 3H), 0.88 (s, 3H). Mass spec (ES+) m/z 494.3 (M+H+, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]1=2
Reactant: CN(C)CCCCl
Reactant: c1cnc2c(c1)N=C(c1ccncc1)c1ccccc1N2
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccncc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(4-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride.
Reaction SMILES: O.[Cl:2][C:3]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:4]=1[CH:5]=[O:6].[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:16]1[C:12]([C:8]2[CH:7]=[C:4]([CH:5]3[O:25][CH2:24][CH2:23][O:6]3)[C:3]([Cl:2])=[CH:10][C:9]=2[F:11])=[N:13][N:14]([CH3:22])[C:15]=1[C:18]([F:21])([F:20])[F:19]
Reactant: OCCO
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(-c2cc(C3OCCO3)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Yield: 61.2 %

Procedure:
In an apparatus equipped with a Dean-Stark trap for azeotropic removal of water, 2.4 g (7.0 mmoles) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde, 0.4 mL (7.7 mmoles) ethylene glycol and a catalytic amount of P-toluenesulfonic acid in 50 mL toluene was heated to reflux for 24 hours. The resultant mixture was concentrated and the residue purified by chromatography to give 1.65 g (61%) of 4-chloro-3-(4-chloro-5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a clear colorless oil; nD25 1.5348.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][C:16]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:18]=2[C:19]#[N:20])[C:10]([Cl:25])=[CH:9][C:8]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][O:26][C:8]1[CH:9]=[C:10]([Cl:25])[C:11]([C:13]2[CH:14]=[N:15][C:16]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:18]=2[C:19]#[N:20])=[CH:12][C:7]=1[C:6]([OH:37])=[O:5])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of 2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoic acid 2-trimethylsilanyl-ethyl ester (1.3 g, 2.2 mmol) and tetrabutyl-ammonium fluoride (6.6 mL, 6.6 mmol, 1 M in THF) in THF (20 mL) was stirred at rt for 30 minutes. The mixture was then concentrated and diluted with ether. The ether layer was washed with water, dried and concentrated to yield 2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoic acid (0.8 g). MS [M+H]+: 485.1; tR=2.96 min (method 1)
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@H:3]([NH:11][C:12]([O:14][C@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:13])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:21])([CH3:20])[C@H:3]([NH:11][C:12]([O:14][C@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:13])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)O[C@H]1CCOC1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)O[C@H]1CCOC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 59A (0.037 g, 0.123 mmol) in dichloromethane (1.2 mL) was added trifluoroacetic acid (1.2 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give the title compound which was used without further purification.
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[CH2:4][CH2:3]1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[ClH:15].[Cl:1][C:9]1[CH:8]=[CH:7][C:6]2[O:2][CH2:3][CH2:4][C:5]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: NCCCc1cccc2c1CCO2
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Product: NCCCc1c(Cl)ccc2c1CCO2
Yield: 91.3 %

Procedure:
A solution of of 3-(2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride (150 mg) and N-chlorosuccinimide (100 mg) in acetic acid (50 ml) was stirred at room temperature overnight. The solution was evaporated to dryness and the residue taken up in water, basified with 2N sodium hydroxide and extracted with dichloromethane. The extracts were dried and evaporated and the residue disolved in a solution of hydrogen chloride in methanol. Evaporation gave the the title compound (159 mg) as an off-white powder after trituration with ether.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:19][C:20]2[S:21][C:22]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:23]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.CSC.N>ClCCl>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[N:24]=[C:20]([NH:19][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:18])[S:21][C:22]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N
Solvent: ClCCl
Solvent: CSC
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
Compound 43 (4.71 g, 9.50 mmol) was dissolved in dichloromethane (100 mL), and dimethyl sulfide (29.4 mL, 400 mmol) and boron trifluoride-diethyl ether complex (24.6 mL, 200 mmol) were added thereto, followed by stirring overnight at room temperature. The reaction mixture was poured into 28% aqueous ammonia, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford the entitled Compound 44 (1.36 g, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][C@H:14]([CH2:22][N:23]=[N+]=[N-])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:26])[CH3:2].Cl[Sn]Cl>CO.C1COCC1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][C@H:14]([CH2:22][NH2:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:26])[CH3:2]
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@H](CN)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-[3-(1-azidomethyl-2-phenyl-ethylamino)-6-chloro-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester (5.67 g, 14.5 mmol) in MeOH (80 ml) and THF (40 ml) was added SnCl2 (4.1 g, 21.8 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, azeotroped with CH2Cl2, and purified by flash chromatography (silica gel, 6% MeOH containing 10% NH4OH in CH2Cl2 to 10%) to give (S)-[3-(1-aminomethyl-2-pheny-ethylamino)-6-chloro-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester as a beige solid. 1H NMR (CDCl3, 400 MHz): δ 7.35–7.15 (m, 5H); 6.92 (s, 1H); 6.17 (bd, J=8.5 Hz, 1H); 4.88 (s, 2H));); 4.35–4.15(m, 3H); 3.00–2.70 (m, 4H); 1.32 (t, J=6.9 Hz, 3 H); rotation: [α]d=−82.6° (c=0.42, MeOH).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:7][N:8]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1.[CH2:72]([SH:79])[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]([S:79][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:7][N:8]=[N:9]2)=[CH:4][CH:3]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1cnnc2cc(Cl)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1cnnc2cc(SCc3ccccc3)ccc12
Yield: 78.5 %

Procedure:
To a 2-5 ml microwave vial charged with 7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)cinnoline (0.140 g, 0.413 mmol) was added Xantphos (0.048 g, 0.083 mmol), Pd2(dba)3 (0.038 g, 0.041 mmol), dioxane (1.653 ml) DIEA (0.144 ml, 0.827 mmol) and benzyl mercaptan (0.051 ml, 0.434 mmol). The mixture was purged with argon and microwave irradiated at 140° C. for 10 hrs. The mixture was filtered through diatomaceous earth, dried under reduced pressure and the crude residue purified with a 40 g HP silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 50%, 5% DCM throughout) providing 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)cinnoline (0.138 g, 0.324 mmol, 78% yield) as an off-white solid. m/z (ESI) 427.3 (M+H)+.
Reaction SMILES: O[C:2]1([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O=S(Cl)Cl>N1C=CC=CC=1>[C:11]1([C:8](=[C:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[C:9]#[N:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CC(c1ccccc1)C1(O)CCOCC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#CC(=C1CCOCC1)c1ccccc1
Reaction time: 0.42 h

Procedure:
(4-hydroxytetrahydro-2H-pyran-4-yl)(phenyl)acetonitrile (500 mg, 2.301 mmol) was dissolved in pyridine (10 ml). SOCl2 (1.680 ml, 23.01 mmol) was added and the reaction was stirred for 25 minutes then concentrated in vacuo. The crude material was purified by silica gel chromatography on an Isco Companion (5 to 35% EA/hexanes over 20 min, 40 g silica column). The desired fractions were combined and concentrated in vacuo. 450 mg, 98%.
Reaction SMILES: Br[C:2]1(Br)[C:7]2=[N:8][C:9]3[C:14]([C:15](=[O:16])[N:6]2[CH:5]([CH3:17])[CH2:4][CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([NH:25][N:26]=[C:2]2[C:7]3=[N:8][C:9]4[C:14]([C:15](=[O:16])[N:6]3[CH:5]([CH3:17])[CH2:4][CH2:3]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1CCC(Br)(Br)c2nc3ccccc3c(=O)n21
Reactant: NNc1ccccc1
Solvent: CCO
Product: CC1CCC(=NNc2ccccc2)c2nc3ccccc3c(=O)n21
Yield: 75 %

Procedure:
3.74 g (0.01 mole) of 6,6-dibromo-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b)quinazoline and 4.32 g. (0.04 mole) of phenyl hydrazine are heated in 40 ml. of ethanol for 10 hours. The precipitated crystals are filtered after cooling. The filtered product is suspended in 100 ml. water containing 2.72 g. (0.02 mole), sodium acetate, filtered and washed with water. 2.4 g. (75%) orange 6-phenylhydrazono-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline are obtained which after recrystallization from ethanol melts at 185°-187° C.