Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1

Procedure:
A solution of 1-(3-bromophenyl)but-3-en-1-ol (17.0 g, 74.9 mmol), 1H-imidazole (11.8 g, 172.2 mmol) and tert-butyldimethylchlorosilane (13.9 g, 89.8 mmol) in DMF (40 mL) is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product is purified by silica gel chromatography eluting with 5% ethyl acetate in hexanes to give the title compound as racemic mixture (23.9 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34 (d, 1H, J=7.5 Hz), 7.24-7.14 (m, 2H), 5.78-5.70 (m, 1H), 5.02-4.97 (m, 2H), 4.65-4.62 (m, 1H), 2.45-2.31 (m, 2H), 0.87 (s, 9H), 0.02 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C1COCC1>[C:1]([NH:5][CH2:6][C:7]1[C:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: NCc1ncccc1CCc1ccccc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ncccc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add dropwise with stirring a solution of 1.24 gm acetyl chloride in 10 ml THF to a cooled solution of 3.2 gm of 2-aminomethyl-3-(2-phenylethyl)pyridine and 2.3 ml triethylamine in 100 ml THF. Warm the reaction mixture to room temperature and then stir for an additional 0.5 hour. Filter off the triethylamine hydrochloride and evaporate the filtrate under reduced pressure. Chromatograph on silica gel using 40% THF in chloroform to obtain 2-acetamidomethyl-3-(2-phenylethyl)pyridine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:10])[F:11])[CH:18]=[CH:17][N:16]=1
Reactant: FC(F)(F)c1ccccc1S
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccccc1Sc1ccnc(Cl)c1
Yield: 93 %

Procedure:
Using the method of Example 3, Step A, 2-(trifluoromethyl)benzenethiol (1.12 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol) and 2-chloro-4-nitropyridine (1.00 g, 12.6 mmol) were reacted to provide 2-chloro-4-(2-(trifluoromethyl)phenylthio)pyridine (1.70 g, 93% yield) as an oil. 1H NMR (CDCl3) δ 8.13 (d, 1H), 7.88 (m, 1H), 7.61-7.72 (m, 4H), 6.85 (s, 1H), 6.80 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH2:24]O)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH2:24][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cc(=O)n(CCO)nc2-c2ccc(OC)cc2)cc1
Agent: [Cl-]
Product: COc1ccc(-c2cc(=O)n(CCN3CCOCC3)nc2-c2ccc(OC)cc2)cc1
Yield: 42.6 %

Procedure:
After 5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one was reacted with paratoluenesulfonyl chloride in a similar manner as in Example 116-(2), a further reaction was conducted with morpholine, whereby the title compound was obtained in a yield of 42.6%.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH3:5].[C:6]([O:9]C(=O)C)(=[O:8])[CH3:7].N1C=CC=CC=1>CCOCC>[C:6]([O:9][CH:3]([CH2:4][CH3:5])[CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: C=CCCC
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CC(CC)OC(C)=O
Temperature: 0 °C

Procedure:
The above pentene derivative (9.0 g, 25 mmols) and acetic anhydride (3.0 g, 30 mmols) are dissolved in ether (200 ml), followed by dropwise adding pyridine (5 ml), while stirring the solution under ice cooling, stirring the reaction liquid under ice cooling for one hour, elevating the temperature up to room temperature, stirring for 3 hours, pouring the reaction mixture into ice water after completion of the reaction, extracting with toluene (150 ml), washing the organic layer with water, drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 5-(4-(4-propylphenyl)phenyl)cyclohexyl)-3-acetyloxy-1-pentene pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:15][S:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1)(=[O:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:20]=2)[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
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: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
Into a microwave vial was added 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.040 g, 0.14 mmol), [5-(methylsulfonyl)pyridin-3-yl]boronic acid (0.035 g, 0.17 mmol), 1.0 M sodium carbonate (0.35 mL, 0.35 mmol), 1,4-dioxane (0.87 mL) and tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.0086 mmol). The mixture was bubbled with N2 for 5 min, then heated at 100° C. overnight. The cooled reaction mixture was purified on silica gel to give the desired product (0.035 g, 71%). LCMS calculated for C16H17ClNO4S (M+H)+: m/z=354.1. found: 354.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1.S(Cl)([Cl:22])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(CCCCOCCCCBr)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(CCCCOCCCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-{4-[(4-bromobutyl)oxy]butyl}benzoic acid (0.91 g, 2.77 mmol, e.g. which can be as prepared in Intermediate 25) in thionyl chloride (SOCl2, 2 ml) was stirred at room temperature for 1 hour and then at 100° C. for 2 hours. The reaction mixture was cooled and the excess thionyl chloride was removed by evaporation, followed by co-evaporation with dichloromethane (2×30 ml) to give the title compound as a brown oil (1.03 g). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.5-2.0 (10H, m); 2.75 (2H, m); 3.45 (4H, m); 7.35 (2H, d); 8.05 (2H, d). The compound was not pure by 1H NMR (CDCl3), but it was not purified further.
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C)=O.[NH2:32][CH:33]([C:35]1[N:40]=[N:39][C:38]([NH:41][C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:37][CH:36]=1)[CH3:34].[N+:54]([C:57]1[NH:61][C:60]([C:62](O)=[O:63])=[CH:59][CH:58]=1)([O-:56])=[O:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[N+:54]([C:57]1[NH:61][C:60]([C:62]([NH:32][CH:33]([C:35]2[N:40]=[N:39][C:38]([NH:41][C:42]3[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=3)=[N:37][CH:36]=2)[CH3:34])=[O:63])=[CH:59][CH:58]=1)([O-:56])=[O:55]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc([N+](=O)[O-])[nH]3)nn2)cc(OC)c1OC
Yield: 75.6 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 5-nitro-1H-pyrrole-2-carboxylic acid (132 mg, 0.85 mmol), diisopropylethylamine (0.33 mL, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.94 mmol) in dimethylformamide (5 mL) gave 5-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-pyrrole-2-carboxamide (218 mg, 75%) as a yellow solid. MS m/z 443 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Sn](C)(C)C)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3]1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:33][C@H:32]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[O:31][N:30]=2)=[CH:25][CH:24]=1>>[Si:36]([O:35][CH2:34][C@@H:32]1[O:31][N:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3][C:2]4=[O:1])=[CH:8][CH:9]=3)=[CH:28][CH:27]=2)[CH2:33]1)([C:39]([CH3:42])([CH3:40])[CH3:41])([CH3:38])[CH3:37]
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC(c2ccc(Br)cc2)=NO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@@H](CO[Si](C)(C)C(C)(C)C)C4)cc3)cc2)C(=O)O1

Procedure:
The procedure of Example 41, but starting from N-({(5S)-2-oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (476 mg, 1.20 mM) and (5R)-3-(4-bromophenyl)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazole (370 mg. 1.00 mM) was used to give the desired product after 7 hours at 90° C. Purification by chromatography on silica gel using 90% ethyl acetate/hexanes gave 398 mg of the title product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([C:24]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[OH:25])=[N:20]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([C@@H:57]([O:60][Si:61]([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62])[CH2:58]Br)=[C:50]2[C:55]=1[NH:54][C:53](=[O:56])[CH:52]=[CH:51]2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([C@@H:57]([O:60][Si:61]([C:64]([CH3:65])([CH3:67])[CH3:66])([CH3:63])[CH3:62])[CH2:58][NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([CH2:18][N:19]4[CH:23]=[N:22][C:21]([C@:24]([CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)([OH:25])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:20]4)[CH2:16][CH2:17]3)=[CH:8][CH:9]=2)=[C:50]2[C:55]=1[NH:54][C:53](=[O:56])[CH:52]=[CH:51]2)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: NCCc1ccc(CCN2CCC(Cn3cnc(C(O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 40 %

Procedure:
The title compound was prepared from (R)-({-[(1-{2-[4-(2-aminoethyl)phenyl]ethyl}piperidin-4-yl)methyl]-1H-1,2,4-triazol-3-yl}(cyclohexyl)phenylmethanol (Preparation 13, 2.57 g, 5.12 mmol) and 8-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(1H)-one (WO2005/09286, 2.50 g, 5.12 mmol) using the same method as described in preparation 7 to give a white solid, in 40% yield, 2.3 g.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].N[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=CC=1>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][CH2:1][C:2]1[CH:41]=[N:40][CH:39]=[CH:38][CH:37]=1)=[O:5]
Reactant: NCc1cccnc1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4cccnc4)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 3-(aminomethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13](N)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I:26]CI.N(OCCC(C)C)=O.Cl>[Cu]I.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([I:26])[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1C1=NCc2cnc(I)nc2-c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 49.6 %

Procedure:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride (1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and ethanol (100 mL) were combined in a 100-mL round-bottomed flask and stirred at reflux for 3 hours. The reaction mixture was poured into 500 mL water with stirring. The mixture was extracted with ethyl acetate (4×200 mL). The organic extracts were combined, washed with saline, dried (Na2SO4), filtered, and evaporated to leave a brown solid. The solid was stirred with diethyl ether, filtered, washed with ether, then dried in vacuo to provide 9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper (I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a round-bottomed flask and stirred at reflux for 1 hour. The dark purple solution was cooled to room temperature and then transferred to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic extracts were combined, washed with ammonium hydroxide (3%), saturated ammonium chloride, and saturated saline, and then dried (Na2SO4), filtered, and concentrated to leave a dark oil. Purification by column chromatography (silica gel, CH2Cl2 to 10% ethyl acetate in CH2Cl2) afforded 9-Chloro-7-(2,6-difluoro-phenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[NH3:33]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([NH2:33])=[O:28])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: Cc1cccc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(N)=O)CC4)nc23)c1

Procedure:
Prepared from compound 134 of Example 1 by reaction with thionyl chloride and ammonia.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH:37]=[CH2:38]>C(#N)C.O>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[N:27]([CH2:38][CH:37]=[CH2:36])[CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C=CCN1C2CCC1CC(=C1c3ccccc3Oc3cc(C(=O)N(CC)CC)ccc31)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.3 %

Procedure:
To a sample of compound 10a (0.37 g, 0.95 mmol) in 6 mL acetonitrile was added potassium carbonate (0.53 g, 3.81 mmol) and allyl bromide (80 μL, 0.95 mmol). The mixture was stirred at room temperature for 20 h. The reaction was diluted with water and extracted with CH2Cl2. The combined organic extracts were dried over magnesium sulfate and concentrated. The product was purified by flash column chromatography on silica gel, eluting with 10% 0.5 M NH3 in methanol/CH2Cl2 to yield 0.11 g (0.25 mmol) of Compound 14a. The product was converted into its HCl salt using ethereal hydrogen chloride. MS m/z=429.0 (M+1); 1H NMR 300 MHz (CDCl3) δ 1.1-1.4 (m, 6H), 1.7 (m, 2H), 2.3 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.6 (m, 4H), 4.0 (m, 2H), 4.4 (m, 2H), 4.7 (m, 2H), 5.5-5.9 (m, 4H), 6.3 (m, 2H), 7.1-7.4 (m, 7H).
Reaction SMILES: [OH-].[Na+].[Br:3][CH2:4][C:5](Br)=[O:6].[CH3:8][NH:9][C:10]1[C:11](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH3:15])=[O:13]>ClCCl>[Br:3][CH2:4][C:5]([N:9]([C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:8])=[O:6]
Reactant: O=C(Br)CBr
Reactant: CNc1ccccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccccc1N(C)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
Sodium hydroxide solution (1.5M, 50 ml) was added dropwise to an ice cooled mixture of bromoacetyl bromide (11 g) and methyl N-methylanthranilate (8.2 g) in dichloromethane (250 ml). After the addition was complete (15 min) stirring was continued at room temperature for 20 min. The organic phase was then separated, washed with 1N HCl (50 ml), brine (50 ml), NaHCO3 solution (50 ml), dried (MgSO4) and evaporated to give a colourless oil which crystallised on standing. Trituration with pet-ether (bp 60°-80°) followed by filtration afforded 10.4 g of product as a colourless solid. 1H NMR (360 MHz, CDCl3) δ: 3.23 (3H, s), 3.54 and 3.60 (2H, ABq J=11 Hz), 3.90 (3H, s), 7.40 (1H, d, J=8 Hz), 7.51 (1H, t, J=8 Hz), 7.65 (1H, t, J=8 Hz), 8.04 (1H, d, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1.C(S(C1C=CC(OCCC)=C(B2OC(C)(C)C(C)(C)O2)C=1)(=O)=O)C.Br[C:55]1[C:60]2[N:61]=[CH:62][N:63]=[CH:64][C:59]=2[C:58](=[O:65])[N:57]([CH3:66])[CH:56]=1.BrC1C2N=C(C3C=NN(C)C=3)N=CC=2C(=O)N(C)C=1>>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:55]1[C:60]2[N:61]=[CH:62][N:63]=[CH:64][C:59]=2[C:58](=[O:65])[N:57]([CH3:66])[CH:56]=1
Reactant: Cn1cc(Br)c2ncncc2c1=O
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: CCCOc1ccc(S(=O)(=O)CC)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cn1cc(-c2ncc3c(=O)n(C)cc(Br)c3n2)cn1
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3cncnc23)c1

Procedure:
The title compound of step 2 was substituted for the title compound of Example 225, step 2 and the title compound of Example 231, step 3 was substituted for the title compound of Example 224, step 4 and reacted in a similar manner as Example 225, step 3. 1H NMR (CDCl3, 400 MHz) δ 9.60 (s, 1H), 9.27 (s, 1H), 8.12 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.94 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.32-7.25 (m, 1H), 7.15-7.09 (m, 1H), 7.03-6.97 (m, 2H), 3.70 (s, 3H), 3.27 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). LCMS: 458.0 (M+H)+
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1>CN(C)C=O>[CH3:20][N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][N:25]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:26]2)[CH2:22]1
Reactant: CN1CC2CNCC2C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CN(C)C=O
Product: CN1CC2CN(C(=O)N3c4ccccc4C(=O)Nc4cccnc43)CC2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4.9 g (18 mmoles) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2.3 g of 3- methyl-3,7-diazabicyclo[3.3.0]octane in 75 ml of dry dimethylformamide was stirred for 20 hours at ambient temperature. The reaction mixture was concentrated in vacuo, the residue was divided between 1N hydrochloric acid and methylene chloride. The organic phase was washed two further times using 1N hydrochloric acid and once using water. The combined aqueous phases were rendered basic using potassium carbonate and extracted using methylene chloride (3×150 ml). The combined methylene chloride phases were dried over magnesium sulphate, concentrated and the crude material was recrystallised from acetonitrile. 2.9 g (41% of theory) of colourless crystals of m.p. 157°-159° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[CH2:15][C:16]([O:18]C)=[O:17].O.[Li+].[OH-].Cl>C1COCC1>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1OCC(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C(F)(F)F)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetate (1.07 g, 3.5 mmol) from Step 2 above in THF (8 mL) and water (2 mL) was added LiOH (0.20 g, 4.8 mmol). The mixture was stirred at ambient temperature for 24 h. The reaction was acidified to pH 2 with 5 N aqueous HCl and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-50% MeOH:CH2Cl2 to give 2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetic acid as a gum (HPLC retention time=8.7 min (method A)).