Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:8]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:33]>CCOC(C)=O.O1CCOCC1>[ClH:33].[Br:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:8]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(NC(=O)Cn2c3c(c4cccc(Br)c42)CCN(C(=O)OC(C)(C)C)CC3)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1csc(NC(=O)Cn2c3c(c4cccc(Br)c42)CCNCC3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
tert-Butyl 7-bromo-6-{2-[(4-methyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.280 g, 0.52 mmol) was dissolved in EtOAc (15 mL). 4N HCl in dioxane (5 mL) was added and the reaction mixture was stirred at rt under N2. After 1 h, a white solid precipitated from the solution. The precipitate was collected by filtration. Pure 2-(7-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide hydrochloride was obtained after recrystallization from 3:1 CH3OH:Et2O (20 mL), as a white solid (0.220 g) in 94% yield. 1H NMR (400 MHz, CD3OD) δ 2.4, 3.22-3.28, 3.49-3.59, 5.7-5.78, 6.88, 7.02, 7.35, 7.54; MS (ESI+) for C18H19BrN4OS m/z 420.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Nc4cccc(Cl)c4)nc23)S1
Temperature: 180 °C

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (20 mg, 0.06 mmol) in NMP was added 3-chloroaniline (38 μL, 0.36 mmol) and a few granules of p-toluenesulfonic acid. The reaction was heated in microwave at 180° C. 1.5 hours. The reaction mixture was filtered and purified by prep HPLC then prep TLC (1% MeOH/DCM) to yield 5-((5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione as a yellow solid. LCMS (M+1=427)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22](Br)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([Sn](CC)(CC)CC)[CH3:41]>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.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Sn](CC)(CC)CC
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(CC)c1
Yield: 50.7 %

Procedure:
Ethyl 1-benzyl-3-[(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (2.07 g), tetraethyltin (2.07 g), tetrakis(triphenylphosphine)palladium (0.40 g) and toluene (50 mL) was stirred under an argon atmosphere while heating under reflux for 3 days. After concentration of the reaction mixture, the residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (0.96 g, 51%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=O.C(O)C>CO>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[N:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CCO
Solvent: CO
Product: O=C(O)Cc1cccc(N=Cc2cc(Cl)ccc2O)c1
Yield: 69.6 %

Procedure:
Using the procedure of Sheeman et al [J.A.C.S., Vol. 84, (1982), p. 2457], 1.5 g of 3-amino-phenylacetic acid, 1.72 g of 5-chloro-2-hydroxy-benzaldehyde, 480 ml of 100% ethanol and 35 ml of methanol were reacted to obtain 2 g of 3-[(5-chloro-2-hydroxy-benzylidene)-amino]-phenylacetic acid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>O1CCOCC1.C(OCC)(=O)C>[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1ccccc1
Reactant: Nc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1cncc(OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a stirred solution of benzyl alcohol (432 μL; 4.0 mmol) in dioxane (2 mL) was added sodium hydride (96 mg; 4.0 mmol). After stirring for 30 minutes, 2-amino-6-chloropyrazine (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), and brine (30 mL), then dried (MgSO4). and filtered. The crude product was purified using the biotage 12i cartridge eluting with hexane and ethyl acetate (3:1) to yield a white solid (33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[O:31]=[S:26]1(=[O:32])[CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 86.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 211 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (386 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:20])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2,6-dichlorophenyl acetic acid (100 g, 487 mmol) and DMF (1.5 mL) in toluene (600 mL) was added thionyl chloride (116 g, 974 mmol). The resulting mixture was stirred at rt. After 12 h, the solution was concentrated to provide 2,6-dichloro-phenylacetyl chloride as colorless oil. MS (ESI): mass calcd. for C8H5Cl3O, 221.94; m/z found, 223.0 [M+H]+. 1H NMR (CDCl3): 7.33 (d, J=8.1 Hz, 2H), 7.29-7.24 (m, 1H), 4.56 (s, 2H). A suspension of the crude 2,6-dichloro-phenylacetyl chloride and 4,6-dichloro-pyrimidin-5-ylamine (76 g, 463 mmol) was heated neat to 130° C. After 1 h, the resulting solid was cooled, collected by filtration, and washed with cold MeOH (400 mL) to provide the title compound as a solid (135 g, 84%). MS (ESI): mass calcd. for C12H7Cl4N3O, 348.9; m/z found, 350.0 [M+H]+. 1H NMR ((CD3)2SO): 10.59 (s, 1H), 8.86 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.37-7.33 (m, 1H), 4.13 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[N:5][S:4][N:3]=1.[Br:14]N1C(=O)CCC1=O.O.C([O-])([O-])=O.[K+].[K+]>ClC(Cl)(Cl)Cl>[Br:14][CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:6]1[C:2]([Cl:1])=[N:3][S:4][N:5]=1
Reactant: Cc1ccncc1-c1nsnc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1nsnc1-c1cnccc1CBr
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-4-methylpyridine (0.63 g, 3 mmol) in tetrachloromethane (50 ml) was added under nitrogen, N-bromosuccinimide (0.80 g, 4.5 mmol) and α,α-azoisobutyronitril (80 mg, 0.5 mmol). The reaction mixture was stirred at 75° C. overnight. Water (50 ml) was added and after basifying with K2CO3 the reaction mixture was extracted with methylene chloride (3×100 ml). The organic phases were dried (MgSO4) and evaporated. The residue contained a mixture of starting material, the monobromo and the dibromo product. Separation by column chromatography, eluent: ethyl acetate/methylene chloride: 1/10, gave the title compound in 180 mg (20%) yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[CH2:10]([O:17][C:18]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Trans-4-hydroxy-L-proline (4.7 g) was dissolved in 2N sodium hydroxide (36 ml), to which benzyloxycarbonylchloride (6.1 g) was slowly added dropwise under cooling with ice water. The mixture was then stirred at room temperature throughout a whole day and night. After the reaction, the mixture was washed with ethyl acetate, and to the aqueous layer was then added sodium chloride to saturation. Then the pH was adjusted to around 3 with 10N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated solution of sodium chloride in water and it was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure whereby the titled compound (6.9 g) was obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:30][CH2:29]5)=[N:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (270 mg. 0.41 mmol) was alkylated using (S)-2-methyloxirane (48 mg, 0.82 mmol), DIPEA (159 mg, 1.23 mmol) and ethanol (10 mL) to get 350 mg (crude) of the titled compound. MS: m/z=680.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:28][CH2:29][CH2:30][OH:31].Cl>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCNCC4)n3)ccc21
Reactant: OCCCCl
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCN(CCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 95 mg (0.244 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-1,4-diazepane and 30 μl (0.321 mmol) of 3-chloropropan-1-ol. The product is in the form of the hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C(P(=O)(OCC)OCC)#N>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:26])[NH:35][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: COc1ccc(CN)cc1
Agent: CCOP(=O)(C#N)OCC
Product: COc1ccc(CNC(=O)Cc2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)cc1
Yield: 78.6 %

Procedure:
[1-(tert-Butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (70 mg, 0.19 mmol) was treated with 4-methoxybenzylamine (31 mg, 0.22 mmol), diethyl cyanophosphonate (36 mg, 0.22 mmol), and TEA (38 mg, 0.37 mmol) according to the procedure described in example 1E to give {6,7-dimethoxy-4-[(4-methoxy-benzylcarbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester (74 mg, 80.7%). H1-NMR (CDCl3): 8.19 (s, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 6.97 (d, 2H, J=8.8 Hz), 6.73 (d, 2H, J=8.5 Hz), 6.14 (m, 1H), 5.62 (m, 1H), 4.87 (d, 2H, J=4.3 Hz), 4.26 (d, 2H, J=6.0 Hz), 4.03 (s, 2H), 3.94, 3.91, and 3.75 (s, 3H each), 1.50 (s, 9H); MS: APCI (M+H) calc'd for C27H33N3O6+H 496.6; found 496.0.
Reaction SMILES: CN(C[CH:5]([C:10]1[N:11]=[CH:12][S:13][CH:14]=1)[S:6][CH2:7][CH2:8][NH2:9])C.[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[N:28]=[CH:29][N:30]([CH:32]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH:31]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:29][N:30]([CH2:32][C:12]1[S:13][CH:14]=[C:10]([CH2:5][S:6][CH2:7][CH2:8][NH:9][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[N:28]=[CH:29][N:30]([CH:32]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[CH:31]=3)=[CH:21][N:20]=2)[N:11]=1)[CH3:31]
Reactant: CN(C)CC(SCCN)c1cscn1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2cnc(Cc3cnc(N[N+](=O)[O-])[nH]c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(C(c2ccc(OC)cc2)n2cnc(Cc3cnc(NCCSCc4csc(CN(C)C)n4)[nH]c3=O)c2)cc1
Yield: 50.7 %

Procedure:
A solution of 2-(dimethylaminomethyl-4-thiazolylmethylthio)ethylamine (2.3 g) and 2-nitroamino-5-[1-(4,4'-dimethoxybenzhydryl)imidazol-4-ylmethyl]-4-pyrimidone (4.62 g) in ethanol (11 ml) was refluxed for 22 hours. Ethanol was evaporated from the solution and the residue chromatographed using HPLC. The appropriate fractions were combined and freed of solvents to give about 1.6 g of 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-[1-(4,4'-dimethoxybenzhydryl)imidazol-4-ylmethyl]-4-pyrimidone as a glass.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[O:9]C(=O)[NH:7]1.[Li+].[OH-]>CCO.O>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:12]2[C@@H:11]([C@@H:10]([OH:9])[C@@H:6]([NH2:7])[CH2:5][C:4]3[CH:31]=[C:32]([F:34])[CH:33]=[C:2]([F:1])[CH:3]=3)[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step A (8), 420 mg, 0.9 mmol) in EtOH (20 mL) was added a solution of LiOH (217 mg, 9 mmol) in H2O (5 mL). This reaction mixture was brought to 60° C. and stirred overnight. The mixture was then concentrated in vacuo. Ethyl ether (100 mL) was added to the mixture and washed with 1N HCl (80 mL) twice. The aqueous phase was basified to pH 12 with 50% aqueous NaOH solution. This mixture was extracted with ethyl acetate (100 mL) twice. The combined organic layer was dried (Na2SO4), and concentrated in vacuo to give 345 mg of the title compound of Preparation A: 1H NMR (CDCl3, 500 MHz) δ 1.78 (2H, brd s), 2.44 (1H, dd, J=10, 15 Hz), 2.93 (1H, m), 3.01-3.07 (3H, m), 3.36 (1H, s), 3.60-3.69 (3H, m), 3.80 (3H, s), 6.69 (1H, m), 6.77-6.81 (2H, m), 6.86 (2H, d, J=10 Hz), 6.98 (1H, d, J=5 Hz), 7.12-7.18 (3H, m), 7.24 (2H, d, J=10 Hz). MS (ESI)(M+H)+ 439.12.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[C:5]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18]Br)[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:6]=[C:7]([Cl:9])[CH:8]=1>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18][NH2:1])[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: N
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Solvent: ClCCl
Product: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a flask containing ammonia (7.0 M solution in methanol) (132 ml, 927 mmol) was added a solution of 2-[(3-bromo-5-chlorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (4.97 g, 11.59 mmol) in DCM (15 ml) dropwise and the mixture was stirred overnight at room temperature. The solvent was removed and the crude material was purified via silica gel chromatography to give ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (3.70 g, 10.14 mmol, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.34-7.85 (m, 3H), 7.06 (s, 1H), 6.99 (t, 1H), 3.72 (s, 2H), 1.85 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1ccc(Cl)cc1

Procedure:
100 ml of benzene was added to 18.3 grams of p-chlorocinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 80° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:11][OH:12]>N1C=CC=CC=1>[CH3:1][C:2](=[N:11][OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NO
Reactant: CCCCCCC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)=NO
Temperature: 25 °C
Reaction time: 120 h
Yield: 87 %

Procedure:
In a 50 ml round-bottom flask, a mixture of 2-octanone, hydroxylamine hydrochloride in pyridine was stirred, at room temperature under nitrogen blanket, for five days. The reaction mixture was then concentrated under vacuum to remove most of pyridine. The oil was then dissolved in dichloromethane. The product precipitated on standing. The product was obtained as a white solid in 87% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccc(O)cc1
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
Following the procedure of Example 1, 4-(2-nitro-4-trifluoromethylphenylamino) phenol is reacted with ethyl 4-bromo-3-methoxy-2-pentenoate to give ethyl 4-[4-(2-nitro-4-trifluoromethylphenylamino)phenoxy]-3-methoxy-2-pentenoate
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:15][CH2:14][C:5]2=[C:6]([C:11]([OH:13])=O)[S:7][C:8]([S:9][CH3:10])=[C:4]2[CH2:3]1.[CH3:17][Li]>C(OCC)C>[CH3:16][C:2]1([CH3:1])[CH2:15][CH2:14][C:5]2=[C:6]([C:11](=[O:13])[CH3:17])[S:7][C:8]([S:9][CH3:10])=[C:4]2[CH2:3]1
Reactant: CSc1sc(C(=O)O)c2c1CC(C)(C)CC2
Reactant: [Li]C
Solvent: CCOCC
Product: CSc1sc(C(C)=O)c2c1CC(C)(C)CC2
Reaction time: 2 h

Procedure:
To a solution of 5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (508 mg, 1.98 mmol) in diethyl ether (20 mL), a solution of methyllithium (1.1 mL, 1.6 M in diethyl ether) is added at rt. The mixture is stirred at rt for 1 h before another portion of methyllithium (0.25 mL) is added. Stirring is continued for 2 h. The reaction is quenched by the addition of 1 N aq. K2HPO4 solution. The mixture is diluted with diethyl ether, washed with 1 N aq. NaOH, dried over Na2SO4 and evaporated to give 1-(5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (214 mg) as a yellow oil; LC-MS: tR=1.09 min, [M+1]=255.1.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C1Cc2ccc(O)cc2CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1Cc2ccc(OCc3cccc(F)c3)cc2CCN1

Procedure:
In an analogous manner to that described in Example 17 c), the alkylation of 7-hydroxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one [Example 19 b)] by 3-fluorobenzylbromide in the presence of potassium carbonate in 2-butanone yielded the 7-(3-fluoro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one as a white solid; MS: m/e=286 (M+H)+.