Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)=[CH:10][CH:9]=3)[C:14](=[O:22])[C@@H:15]2[CH2:19][O:20][CH3:21])=[O:32])=[CH:26][CH:25]=1
Reactant: COCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)Nc1ccc(Cl)cc1

Procedure:
The title compound is prepared as described in EXAMPLE 436 using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-piperazine-2-one, EXAMPLE 75, and 4-chlorophenyl isocyanate. 1H NMR (DMSO-d6, 300 MHz) δ9.77 (bs, 2H), 8.81 (s, 1H), 8.70 (s, 1H), 8.40 (d, 1H), 7.64 (d, 1H), 7.61 (s, 1H), 7.49 (d, 2H), 7.28 (d, 2H), 4.88 (m, 1H), 4.80 (AB, 2H), 4.19 (m, 1H), 3.96 (m, 1H), 3.74-3.42 (m, 4H), 3.28 (s, 3H). ESI MS, [M+H]+=455,457 (Cl pattern). Anal. (C22H23ClN6O3.TFA.1.5H2O) C, H, N.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29](OCC)=[O:30])[C:11]1=[O:34].[CH2:36]([CH2:38][NH2:39])[OH:37]>>[O:35]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29]([NH:39][CH2:38][CH2:36][OH:37])=[O:30])[C:11]1=[O:34]
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (300 MHz, CDCl3) δ 10.40 (s, 1 H), 8.58 (s, 1 H), 7.88 (s, 1 H), 7.24 (m, 2 H), 7.01 (t, J=8.5 Hz, 2 H), 4.40 (m, 2 H), 4.13 (s, 2 H), 3.87 (m, 2 H), 3.66 (m, 2 H), 3.43-3.36 (m, 4 H), 2.97 (m, 2 H), 2.19 (m, 2 H), 1.60 (m, 2 H); MS m/z 519 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[F:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1c(F)cccc1C(=O)O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(F)c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Fluoro-2-methyl-benzoic acid. LC-MS (basic): tR=0.92 min; [M+H]+=464.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([N:14]2[CH:15]=[CH:16][C:17](=[O:18])[C:12]([C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[CH:9][CH:10]=3)=[N:13]2)[CH2:20]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=c1ccn(-c2cccnc2)nc1-c1ccnn1-c1ccccc1
Solvent: CC#N
Product: O=c1ccn(C2CCCN(Cc3ccccc3)C2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-3-ylpyridazin-4(1H)-one (500 mg) in acetonitrile (5 mL) was added benzylbromide (0.19 mL) at room temperature, and the mixture was heated under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The obtained solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), and platinum dioxide (54 mg) was added. The reaction mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere (3 atm) and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The obtained solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (270 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].O=O.[Br-].[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:13][C:9]1[CH:8]=[C:7]([C:14](=[O:16])[CH3:15])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[O:11][CH3:12])(=[O:22])[CH3:21]
Reactant: CC(=O)OCCCCBr
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Agent: O=O
Agent: [Br-]
Product: COc1c(OCCCCOC(C)=O)cc(C(C)=O)cc1C(C)(C)C
Yield: 100.5 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 6.9 g) was converted and worked up analogously to O2.071. The bromide used was 4-bromobutyl acetate (7.27 g). 10.5 g of the title compound were obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH2:24][CH2:25][CH3:26])=[N:22][N:23]=[C:3]12.C(N(CC)CC)C.[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[C:44](Cl)=[O:45]>C(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH2:24][CH2:25][CH3:26])=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:44]([C:35]2[CH:36]=[CH:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=2)=[O:45])[N:8]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
In 20 ml of chloroform was dissolved 1.5 g of 6-amino-4-(2-chlorophenyl)-2-ethyl-9-propyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine, and 0.47 g of triethylamine was added to the solution. A solution of 0.89 g of naphthalene-2-carbonyl chloride in 10 ml of chloroform was added dropwise to the mixture at not more than 10° C. The mixture was further stirred for 1 hour at room temperature and washed with 0.1N hydrochloric acid, 0.1N sodium hydroxide and a saturated solution of sodium chloride in order. Thereafter, the solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether. Ethanol was added to yield crystals, which were collected by filtration. The crystals were recrystallized from chloroform-ethanol to give 1.4 g of 4-(2-chlorophenyl)-2-ethyl-6-(2-naphthalenecarboxamido)-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, m.p. 226°-227° C.
Reaction SMILES: [I-].[CH2:2]([N+:5]1[C:14]2[C:13]3[O:15][CH2:16][CH2:17][O:18][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:3]=[CH2:4].[OH-:19].[K+].O>O1CCOCC1>[CH2:2]([N:5]1[C:14]2[C:13]3[O:15][CH2:16][CH2:17][O:18][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][C:6]1=[O:19])[CH:3]=[CH2:4]
Reactant: C=CC[n+]1cccc2ccc3c(c21)OCCO3
Reactant: [OH-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1c(=O)ccc2ccc3c(c21)OCCO3
Yield: 64.2 %

Procedure:
10-(2-Propen-1-yl)-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10-ium iodide (5.91 g; 16.65 mmol), KOH (4.10 g; 73.26 mmol) and K3-[Fe(CN)6] (12.05 g; 36.63 mmol) were stirred in 50% aqueous 1,4-dioxane at RT for 1.5 h. Water (250 ml) was added and the aqueous layer was extracted with 10% MeOH/DCM (150 ml) and the organics were washed with water (250 ml). The organics were dried with MgSO4 and the solvents removed. The crude residues were purified by column chromatography on silica gel using a 0-7% MeOH/DCM gradient to give the desired product (2.6 g; 65%). MS (ES+) m/z 244 (MH+).
Reaction SMILES: [CH:1]#[C:2][C@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (R)-(+)-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (R)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 91 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21]N=C[C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CC1C([N+]([O-])=O)=C2C(=CC=1)C=[N:37][CH:36]=C2>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:36]=[N:37][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Product: O=c1c2cc(Cc3ccc(Cl)nc3)c3ncccc3c2ncn1[C@H]1CCCC[C@@H]1O

Procedure:
6-[(6-Chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[2,3-h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one in Example 1, substituting 6-methyl-5-nitroquinoline for 6-methyl-5-nitroisoquinoline.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[N:3][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][S:24]4(=[O:30])=[O:29])=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 51.6 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (49 mg) described in Preparation Example 232 and isothiazolidine 1,1-dioxide (16 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (28 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 6-nitro-7-chloro-1,4-dihydro-2,3-quinoxalinedione (35 mg, 0.145 mMol) in ethanol (2 mL) was added SnCl2.2H2O (163 mg, 0.724 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 0.5 h to form a clear solution and continually refluxed for another 0.5 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (1×1 mL) to give 25 mg (82%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 14 mg of pure title compound as bright yellow needles, mp: >350° C. (dec. from 335° C.). IR (KBr, cm-1): 3406, 3356, 3212, 1668, 1637, 1518, 1437. NMR (1H, DMSO-d6): d 5.306 (s, 2H); 6.551 (s, 1H); 6.940 (s, 1H); 11.606 (s, 1H); 11.788 (s, 1H). HRMS: calcd for C8H6N3O2Cl (M+) m/z: 211.0147; found 211.0159. Potency relative to DCK: 28.0%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH:21]=1.[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[N:18]([CH2:26][CH:25]=[CH2:24])[CH2:19][CH2:20][CH:21]=1
Reactant: COC(=O)CCC1=CCCNC1=O
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1CCC=C(CCC(=O)OC)C1=O
Temperature: -79 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
0.220 ml of NaHMDS solution (1.0 M in THF, 0.22 mmol) was added to 0.5 ml of the THF solution containing 40 mg of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (0.218 mmol) prepared by the Step 1 in a dropwise manner at −79° C. and stirred at −79° C. for 30 mins. After 0.028 ml of allyl bromide (0.327 mmol) was added to the reaction mixture, the mixture was stirred at 0° C. for 3 hrs. The reaction mixture was quenched by 2 ml of sat. NH4Cl solution, and then the organic layer was extracted with 7 ml of ethyl acetate. The combined organic layer was washed with 2 ml of sat. NH4Cl solution and 2 ml of sat. NaCl solution. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc/hexane (1:2) solvent mixture as an eluant to give 36 mg (yield: 74%) of the title compound (i1).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27](OC)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=2)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccc(Cl)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
Trimethylaluminium (5.75 mL, 11.50 mmol) was added to 5-chloropyridin-2-amine (1.285 g, 10.00 mmol) in toluene (50 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes, (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (2.894 g, 10.00 mmol) in toluene (20 mL) was added, the reaction allowed to warm to room temperature and then heated at 80° C. for 4 hours. The reaction mixture was cooled, concentrated in vacuo and the residue neutralised with 1M citric acid (30 mL), diluted with water (25 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford crude product which was purified by flash silica chromatography with EtOAc as eluent to afford the product (2.5 g, 65%). 1H NMR (400 MHz, DMSO) δ 0.01 (6H, s), 0.84 (9H, m), 2.65-2.70 (2H, m), 2.76-2.83 (2H, m), 3.56-3.59 (2H, m), 4.07-4.10 (1, m), 4.28-4.34 (1H, m), 5.78 (1H, s), 7.92 (1H, dd), 8.12 (1H, dd), 8.36-8.37 (1H, m), 9.87 (1H, s); m/z (ESI+) (M+H)+=386; HPLC tR=1.64 min.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]12([CH2:20][OH:21])[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:21][CH2:20][C:12]23[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCC12CCC(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC23CCC(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
Solid para-toluenesulfonyl chloride (0.449 g) was added to a solution of bicyclo-[2,2,2]oct-1-ylmethanol (300 mg) and triethylamine (0.45 ml) in anhydrous acetonitrile (6 ml) under nitrogen. The mixture was stirred at room temperature for 16 hours then heated at reflux for 18 hours, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ether:hexane (1:9) and further purified by preparative normal-phase HPLC on a Dynamax™ Silica column with hexane:ethyl acetate gradient elution to give the sub-title compound as an oil (0.180 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([CH2:7][C:8]#[N:9])=O.O.[NH2:15][NH2:16]>C(O)C>[NH2:9][C:8]1[CH:7]=[C:5]([C:4]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=2)[NH:16][N:15]=1
Reactant: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)[nH]n1

Procedure:
3,4-Dichlorobenzoylacetonitrile (3.0 g) was dissolved in ethanol (15 ml) to which was subsequently added hydrazine monohydrate (0.67 ml) while cooling with ice. The mixture was heatedunder reflux for 5 hours and allowed to cool. Then, the solvent was distilled away under a reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the title compound (1.72 g) as colorless crystals (melting point: 169-170° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.CN(C)C.[C:22]1([CH3:28])[CH:27]=[CH:26]C=CC=1>>[CH:27]1([CH2:26][N:12]([C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)[C:3]2[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:22][CH2:28]1
Reactant: Cc1ccccc1
Reactant: Fc1cccc(C(F)(F)F)c1N=C1NCCN1
Agent: CN(C)C
Product: Fc1cccc(C(F)(F)F)c1N(CC1CC1)C1=NCCN1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
A mixture consisting of 8 gm (0.032 mol) of 2-[(2-fluoro-6-trifluoromethyl-phenyl)-imino]-imidazolidine, 4.6 gm (105% of the stoichiometrically required amount), 5 cc of trimethylamine acid 25 ml of absolute toluene was heated at 120° C for 18 hours in a closed tube. After cooling, the liquid phase was decanted, the solid residue was dissolved in about 150 cc of 1N hydrochloric acid, the solution was extracted several times with ether, and the ethereal extracts were discarded. The acidic aqueous phase and fractionally extracted with ether at stepwisely increasing pH-values (alkalization with dilute sodium hydroxide). The thin-layer chromatographically uniform fractions were combined, dried over Drierite (calcium sulfate) and evaporated to dryness in vacuo. The residue was caused to crystallize by stirring it with petroleum ether, the mixture was suction-filtered, and the filter cake was dried, yielding 5.7 gm (58.4% of theory) of 2-[N-(cyclopropyl-methyl)-N-(2-fluoro-6-trifluoromethyl-phenyl)-amino]-2-imidazoline, m.p. 126°-127° C.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)[CH3:3].Br[CH2:21]CCBr.[OH-].[K+]>C(O)C.O>[O:4]1[C:5]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]3[N:8]([C:7]=2[CH2:21][CH2:3][CH2:2]1)[CH:13]=[CH:12][CH:11]=[CH:10]3
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1cccc[n+]1CC(=O)OCC
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c2c(n3ccccc13)CCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1,2-di-[(ethoxycarbonyl)methyl]pyridinium bromide (1.5 g, 0.0045 mole) and 1,3-dibromopropane (0.45 ml, 0.0045 mole) in ethanol (10 ml) was added over 5 minutes to a stirred solution of potassium hydroxide (0.75 g, 0.0134 mole) in ethanol (15 ml) at 5° C. The mixture was then allowed to warm upto room temperature and stir for 20 h. The reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a brown oil. This was chromatographed on silica gel eluting with ether to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13]I.O>CN(C)C=O.[Na+].[Cl-]>[Cl:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCI
Reactant: Oc1cccnc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cccnc1
Temperature: 25 °C
Yield: 87242 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowly added drop-wise over 15 min to a cold (0-5° C.), stirring slurry of sodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol) in DMF (250 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The gray slurry was cooled to 0-5° C., and 1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30 min. The resulting dark-brown mixture was allowed to stir and warm to ambient temperature over 16 h. Water (500 mL) was added and the mixture was divided into equal parts. Each half was diluted with saturated NaCl solution (200 mL) and extracted with ether (5×200 mL). All ether extracts were combined and concentrated to give 55.1 g (87.3%) of a dark-brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=2[CH:19]=1.Cl>[OH-].[Na+].C1COCC1.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=CN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
In 1N sodium hydroxide (13.0 ml) and THF:ethanol (1:1, 50 ml) was dissolved ethyl 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylate (2.77 g), and the mixture was stirred at room temperature for 15 hours. To the mixture was added 1N hydrochloric acid (12.5 ml), and the mixture was concentrated. To the residue was added water (200 ml), and the mixture was adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate(300 ml×3), and the organic layer was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (2.52 g, 100%).