Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([C@@:19]([N:23]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[O:25])([CH3:22])[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:44])=[O:4].CO.[OH-].[K+]>C1COCC1>[CH2:12]([N:9]1[C:10](=[O:11])[C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:44])[N:7]=[C:8]1[C@@:19]([N:23]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[O:25])([CH3:22])[CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@](C)(c1nc(C)c(C(=O)OC)c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@](C)(c1nc(C)c(C(=O)O)c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 100.1 %

Procedure:
To a solution of 1-benzyl-2-{(R)-[(3-tert-butoxycarbonylamino-propyl)-(1-p-tolyl-methanoyl)-amino]-methyl-propyl}-4-methyl-6-oxo-1,6-dihydro-pyrimdine-5-carboxylic acid methyl ester (2.75 g, 4.55 mmol) in THF (60 mL) was added MeOH (30 mL) followed by 1N KOH (18.2 mL, 18.2 mmol). The resultant solution was heated to 60° C. for 3 h, then concentrated under reduced pressure. The residue was diluted with H2O (75 mL), adjusted to pH˜7 with 1N HCl, and extracted with EtOAc (3×75 mL). The extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.69 g (100%) of 1-benzyl-2-{(R)-[(3-tert-butoxycarbonylamino-propyl)-(1-p-tolyl-methanoyl)-amino]-methyl-propyl}-4-methyl-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid as an oil which was used in the subsequent step without purification: MS (ES) m/e 591.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.Cl.N1C=CC=CC=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>>[Br:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH:37][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Nc1cccc(Br)c1
Yield: 61.9 %

Procedure:
A solution of 400 mg (1.38 mmol) of 4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 8 mL of 2-ethoxyethanol containing 160 mg (1.38 mmol) of pyridine hydrochloride and 0.180 mL (1.65 mmol) of 3-bromoaniline is heated at reflux for 4 hours. The reaction mixture is filtered hot and the solid is stirred with methanol and ammonium hydroxide. The mixture is poured into water and the solid is collected, washing with ethyl acetate to give 363 mg (62%) of 4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile as a brown solid, mp>300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH2:18].N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH:18][S:26]([CH3:25])(=[O:28])=[O:27]
Reactant: COc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cncc(C#Cc2ccc(F)c(NS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 57.4 %

Procedure:
Dissolve 2-fluoro-5-(5-methoxypyridin-3-ylethynyl)-phenylamine, (prepared as described in EXAMPLE 111), (330 mg, 1.36 mmol) in dichloromethane (10 mL) under nitrogen and cool to 0° C. Add pyridine (0.240 ml, 2.99 mmol) followed by methanesulfonyl chloride (0.106 mL, 1.36 mmol) dropwise via syringe. Stir 14 h while allowing to warn to room temperature. Concentrate and purify by silica gel chromatography, eluting with 80:20 ethyl acetate:hexanes to 100% ethyl acetate, to give the title compound as a white solid (250 mg, 57%).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=O)[CH2:2][CH2:3][CH3:4].COC1C=CC(C2(C3C=CC(OC)=CC=3)CC[NH:28]CC2)=CC=1.N>>[NH2:28][C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: COc1ccc(C2(c3ccc(OC)cc3)CCNCC2)cc1
Reactant: CCCC(=O)CC(=O)OCc1ccccc1
Agent: N
Product: CCCC(N)=CC(=O)OCc1ccccc1

Procedure:
A mixture of benzyl butyrylacetate (22.0 g, 0.10 mol) and 10 g of 4 A molecular sieves was treated with ammonia gas which was bubbled through the mixture for 38 hrs at 50° C. After filtration, benzyl 3-amino-2-hexenoate was obtained as a yellowish oil (21 g, 95%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:18]([O:22][C:23](=[O:34])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1)([CH3:21])([CH3:20])[CH3:19].[OH-].[K+]>CCO>[C:18]([O:22][C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:16]/[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[O:17])=[CH:30][CH:31]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)c1ccc(C2CCN(C)CC2)cc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)OC(C)(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.1 %

Procedure:
A mixture of 1-[4-(1-methyl-piperidin-4-yl)-phenyl]-ethanone hydrochloride (544 mg, 2.15 mmol), 4-formylcinnamic acid tert-butyl ester (500 mg, 2.15 mmol) and 1.7 M KOH (3.8 ml, 6.46 mmol) in EtOH (10 ml) was stirred at room temperature for 6 hours. During the reaction, the formation of a precipitate was observed. The solid was then filtered off through a Buchner funnel to obtain 270 mg of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7]C)=[O:6].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:14]>C1C=CC=CC=1>[ClH:14].[N:9]1([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: COC(=O)CCCI
Agent: Cl
Solvent: c1ccccc1
Product: O=C(O)CCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30.0 g. (0.13 mole) of Methyl γ-iodobutyrate (F.F. Blicke, W.B. Wright and M.F. Zienty, J. Amer. Chem. Soc. 63, 2488 (1941) was combined with 36 g. of pyrrolidine (Aldrich) in 300 ml. of benzene, heated at 60° for 0.5 hour and stirred at room temperature for 16 hours. A dark orange layer formed. The benzene solution was decanted, concentrated and distilled (b.p. 100° at 15 mm Hg) to give 10 g. of colorless liquid. The infrared and nmr spectra indicated that product to be methyl Γ-pyrrolidinobutyrate. This material was dissolved in 100 ml. of 18% hydrochloric acid and heated at reflux for 28 hours. The solution was concentrated under reduced pressure to give a semi-solid which was triturated with acetone and filtered. Recrystallization from acetic acid/acetone gave 8.3 g. (33%) of the desired acid hydrochloride as colorless crystals, m.p. 126°-127°. The infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]2)[CH3:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>C(Cl)Cl.CN(C=O)C>[CH:26]1([NH:29][C:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([CH2:10][N:8]([C:5]3[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=3)[CH3:9])[CH2:16][CH2:15]2)=[O:19])[CH2:28][CH2:27]1
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)c1ncc(Br)cn1
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.50 g (1.52 mmol) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid in 4.5 mL of CH2Cl2 was treated at RT with 1 drop of DMF followed by 0.14 mL (1.68 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, the residue was redissolved in CH2Cl2 and added dropwise to a solution of 2.14 mL (30.47 mmol, 20 eq) of cyclopropylamine in 3 mL of CH2Cl2 at 0° C. The reaction was warmed to RT and left for 3 h, then partitioned between Et2O (×3)/aqueous 10% NaHCO3, washed once with aqueous 10% NaHCO3, dried over Na2SO4 and evaporated to yield 0.55g (99%) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid cyclopropylamide, MS: 367 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
A mixture of (R)-tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.25 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1,4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90° C. for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64%) of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[C:26]([O:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: C=CC1(CO)COC(=O)C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1(COC(=O)CCCCCCCCCCCCC)COC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of 8b (0.2 g, 1.4 mmol) in CH2Cl2 (20 mL) was treated with pyridine (0.45 mL, 5.6 mmol), dimethylaminopyridine (0.034 g, 0.28 mmol), and tetradecanoyl chloride (0.76 mL, 2.8 mmol). After stirring for 2 h at room temperature, the reaction mixture was concentrated, and residue was purified by flash column chromatography over silica gel with hexane:EtOAc (3:1) as eluant to give 8c (0.49 g, 99%) as an oil: IR (neat) 1788 and 1741 cm-1 (C=O); 1H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.25 (m, 20 H, CH3 (CH2)10CH2CH2CO), 1.60 (m, 2 H, CH3 (CH2)10CH2CH2CO), 2.31 (t, J=7.4 Hz, 2 H, CH3 (CH2)10CH2CH2CO), 2.60 (s, 2 H, H-3), 4.12 (AB q, J=11.3 Hz, 2 H, CH2OCOC13H27), 4.20 (AB q, J=9.3 Hz, 2 H, H-5), 5.19 (d, J=17.6 Hz, 1 H, CH=CHH), 5.28 (d, J=10.9 Hz, 1 H, CH=CHH), 5.84 (dd, J=10.9, 17.6 Hz, CH=CH2), 13C NMR (CDCl3) δ 14.02, 22.58, 24.69, 28.99, 29.11, 29.24, 29.34, 29.48, 29.53, 29.56, 31.81, 33.93, 36.57, 45.76, 66.63, 73.60, 116.63, 136.81, 173.27, 175.03. Anal. Calcd for C21H36O4 : C, 71.55; H: 10.30. Found. C, 71.46; H, 10.30.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C@H:15]2[CH2:18][C@H:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)[C:13]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C@H:17]1[CH2:18][C@H:15]([N:14]2[C:13]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [(S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl]carbamic acid tert-butyl ester (0.46 g, 1.05 mmol) in DCM (10 mL) was added TFA (4 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting pale red gummy residue dissolved in DCM and loaded onto an SCX-2 (20 g) cartridge. The cartridge washed with DCM then MeOH and then 2M NH3 in MeOH solution. The relevant fractions were concentrated in vacuo to afford the title compound as yellow gum (0.28 g, 80%). LCMS (Method B): RT 2.17 min [M+H]+ 340
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].N1CCCCC1>C(O)C>[NH2:9][C:8]1[O:19][C:18]2[C:25]([CH:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=3)[C:7]=1[C:10]#[N:11])=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=2
Reactant: COc1cc(C=C(C#N)C#N)cc(Br)c1OC
Reactant: Oc1cccc(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C2C(C#N)=C(N)Oc3cc(O)ccc32)cc(Br)c1OC
Yield: 59.5 %

Procedure:
To a mixture of 3,4-dimethoxy-5-bromobenzylidenemalononitrile (293 mg, 1 mmol) and resorcinol (110 mg, 1 mmol) in ethanol (2 mL) was added piperidine (0.1 mL, 1 mmol). The mixture was refluxed for 2 h. The solvent was evaporated, the residue was purified by chromatography on silica gel with EtOAc and hexane (1:2) as eluant, yielding 240 mg (59.5%) of the title compound. 1H NMR (DMSO-d6): 9.77 (brs, 1H), 6.96–6.86 (m, 5H), 6.52 (d, J=8.1, 1H), 6.41 (s, 1H), 4.65 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[CH2:10]([C:9]1[C:4]([NH2:1])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:11]
Reactant: C=Cc1cccnc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cccnc1N
Yield: 83.9 %

Procedure:
130 mg of the 2-nitro-vinylpyridine [120-1] was dissolved in 5 mL of ethanol, 65 mg of 10% palladiumcarbon catalyst was added thereto, and stirred overnight at room temperature in a hydrogen atmosphere. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and 88.7 mg of 3-ethylpyridin-2-amine [120-2] was obtained as a yellow oily product.
Reaction SMILES: [CH3:1][Mg]Cl.CC1(C)C(C)(C)[O:8][B:7]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[N:16][CH:17]=2)[O:6]1>C1COCC1>[OH:19][CH:18]([C:15]1[N:16]=[CH:17][C:12]([B:7]([OH:6])[OH:8])=[CH:13][CH:14]=1)[CH3:1]
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(B(O)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 M Methylmagnesium chloride in THF (0.4 mL, 0.4 mmol) was added dropwise to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbaldehyde (50 mg, 0.2 mmol, Frontier Scientific, catalog #F2110) in THF (2 mL) at 0° C. After stirring for 1 h at room temperature, the reaction was quenched with 1 N NH4Cl and was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the crude [6-(1-hydroxyethyl)pyridin-3-yl]boronic acid. This was used in the next step without purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8](=[O:9])[CH2:7][S:6][C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]1=2.[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Cl>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:3]1[C:8](=[O:9])[CH2:7][S:6][C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]1=2
Reactant: O=C1CSc2ncccc2N1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCCN1C(=O)CSc2ncccc21
Reaction time: 8 h

Procedure:
A 50% oil dispersion of NaH (7.8 g; 0.16 mole) is added to a stirred suspension of 26 g (0.16 mole) of 1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one in 525 ml of toluene and the mixture gradually warmed, effervescence occurs at about 90°. After heating to reflux for 45 minutes, the mixture is cooled to 30°, treated with 120 ml (0.22 mole) of a 1.8 N toluene solution of 3-dimethylaminopropyl chloride and refluxed for 4 hours. After standing overnight, the mixture is worked up as described in Example 1, part A, to give 23 g of crude base. This is combined with 10 g of base from an earlier experiment and distilled; yield, 27.3 g; bp. 166°-169°/0.2 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[CH:5]=[C:4]([N+:11]([O-])=O)[C:3]=1[CH2:14][C:15]([OH:17])=[O:16].C(N(CC)CC)C>CO.[Pd]>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[CH:5]=[C:4]([NH2:11])[C:3]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1cc([N+](=O)[O-])c(CC(=O)O)c(Cl)c1O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(N)c(CC(=O)O)c(Cl)c1O
Reaction time: 3 h
Yield: 139 %

Procedure:
To 2-chloro-3-hydroxy-4-methoxy-6-nitrophenylacetic acid (52 g) in methanol (600 ml) was added triethylamine (56 ml) and 10% palladium on carbon (4 g). The mixture was hydrogenated for 3 hours at 1.4 bar, filtered, evaporated and the residue crystallised to give the triethylamine salt of 2-chloro-3-hydroxy-4-methoxy-6-aminophenylacetic acid (64 g); NMR (DMSO-d6 /CD3COD/CF3COOD) 1.17(t,9H); 3.05(s,6H); 3.54(s,2H); 3.73(s,3H); 6.4(s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: Fc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (i) using 4-bromo-2-fluorobenzenesulfonyl chloride and fluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([C:26]([F:25])([F:34])[F:35])[CH:28]=3)=[O:20])=[CH:23][CH:24]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 30 %

Procedure:
To a solution of methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol) in dry toluene was added 3-trifloromethyl aniline (0.070 g, 0.43 mmol) followed by addition of trimethyl aluminium (2M solution in toluene) (0.5 mL). The reaction mixture was refluxed for 1 h. The reaction mass was quenched in water and acidified with dilute HCl and extracted in DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford crude product, which was column purified to afford 0.040 g of desired product. 1H NMR (DMSO-d6): δ 7.45-7.54 (m, 2H), 7.59 (m, 2H), 7.72 (q, J=6.3 Hz, 1H), 8.05-8.12 (m, 5H), 8.25 (s, 1H), 10.58 (br s, 1H), 12.77 (br s, 1H); MS (m/z): 477.08 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]1[N:29]=[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([Cl:40])[CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=2)[N:21]=1>CC(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:20]2[N:29]=[C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([Cl:40])[CH:33]=3)[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=3)[N:21]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc(CNc2nc(Cl)nc3ccc(C#N)cc23)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc3n2)CC1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
3.5 g of ethyl isonipecotate, 2.25 g of triethylamine and 30 ml of 2-propanol were added to 1 g of 2-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes and cooled to room temperature. The crystals thus precipitated were recovered by filtration and washed with water and ethanol successively to give 1.13 g of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[C:11](=O)[CH2:10][CH2:9][C:8]([NH:19][C:20](=[O:22])[OH:21])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1>CCOCC.C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:8]([O:21][C:20](=[O:22])[NH:19][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:10][C:11]2([CH2:2][CH2:1]2)[N:6]([CH3:5])[CH2:7]1)([CH3:13])([CH3:9])[CH3:7]
Reactant: CN1CC(NC(=O)O)(c2ccccc2)CCC1=O
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CC(NC(=O)OC(C)(C)C)(c2ccccc2)CCC12CC2
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 11 %

Procedure:
A solution of 333 ul (1.0 mmol) of a 3M ethyl magnesium bromide solution in ether in 4 ml THF was cooled to −70° C. A solution of 124 ul (0.42 mmol) titanium isopropoxide in 0.4 ml THF was added dropwise. The light brown mixture was stirred for 2 minutes. A solution of 122 mg (0.4 mmol) rac-(1-Methyl-6-oxo-3-phenyl-piperidin-3-yl)-carbamic acid ter!-butyl ester (example A.22, step 2) in 2.4 ml THF was added dropwise. The mixture was allowed to warm to room temperature and was stirred for 3 hours. The mixture was cooled in an ice bath and quenched with a 20% ammonium chloride solution. Water and ethyl acetate were added. The white suspension was filtered through a pad of dicalite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 14 mg (11%) of the title compound as a colorless oil. MS (m/e): 317.2 (M+H).