Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29](O)=[O:30]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:29]([CH:25]3[CH2:26][CH2:27][CH2:28][O:24]3)=[O:30])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: O=C(O)C1CCCO1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3CCCO3)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 26 mg (0.22 mmol, 1.1 eq.) of tetrahydrofuran-2-carboxylic acid were reacted according to General Method 1. Yield: 67 mg (81% of theory)
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:27])=[CH:22][CH:21]=1.C(OC(C)=O)C.O>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:25][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5]3)(=[O:35])=[O:36])=[CH:30][CH:29]=2)=[CH:38][CH:39]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc12

Procedure:
Stir a mixture of 3-isopropyl indole in dry DMF (20 ml) under N2 add potassium t-butoxide 1.0 M (1.2 ml, 1.2 mmol) dropwise. Stir the resulting solution for 30 minutes at ambient temperature. Add 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.360 g, 0.1.1 mmol) portionwise and stir the resulting mixture overnight. Pour the reaction mixture into a mixture of EtOAc—H2O. Separate the EtOAc layer, extract with H2O wash with brine and dry (MgSO4) Filter and evaporate to give the crude product. Chromatograph on the ISCO eluting with hexane-EtOAc to give a white solid (0.150 g). Mass spectrum (m/e) (M+H) 451.1492; found 451.1488.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][NH:10][O:11][CH3:12]>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:10]([O:11][CH3:12])[CH3:9])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCCCl
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL of dry methylene chloride) was added 10.4 g of N,O-dimethylhydroxylamine hydrochloride. The mixture was stirred under nitrogen and maintained below 25° C. by cooling in an ice bath as necessary while triethylamine (29.1 mL)was added dropwise over about 20 minutes, resulting in precipitation. After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with an additional 100 mL of saturated sodium bicarbonate, and the aqueous fractions were back-extracted with ether. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give 10.5 g (90%) of an oil, which had satisfactory purity by 1H NMR (CDCl3). Mass spectrum (PB-NH3 /CI): m/e=166 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20](OC)=[O:21])[C:5]2[C:6]3[C:17](=O)[CH2:16][N:15]4[C@:11]([CH3:19])([CH2:12][CH2:13][CH2:14]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1.C(O)(=O)C.O.[NH2:29][NH2:30].O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:30][N:29]=[C:17]3[CH2:16][N:15]4[CH2:14][CH2:13][CH2:12][C@:11]4([CH3:19])[C:7]4[NH:8][C:9]([CH:10]=1)=[C:5]2[C:6]=43
Reactant: COC(=O)c1cc(F)cc2[nH]c3c(c12)C(=O)CN1CCC[C@]31C
Reactant: NN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12CCCN1CC1=NNC(=O)c3cc(F)cc4[nH]c2c1c34
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A solution of compound (R)-methyl 9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate (90 mg), acetic acid (0.54 g), and hydrazine hydrate (0.28 g) in methanol (30 mL) was heated at reflux. After 5 h, the reaction was cooled and water (5 mL) was added. The mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL) and dried over MgSO4. The mixture was filtered, and the filtrate was evaporated to dryness, and the residue was purified by Pre-TLC using CH2Cl2 as eluent to give 80 mg of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.30 (d, 1H, J=9.6 Hz), 7.20 (d, 1H, J=10.2 Hz), 3.76 (d, 1H, J=16.4 Hz), 3.34 (d, 1H, J=16.4 Hz), 2.99-3.02 (m, 1H), 2.54-2.58 (m, 1H), 2.35-2.40 (m, 1H), 1.90-1.94 (m, 1H), 1.73-1.75 (m, 1H), 1.48 (s, 3H), and 1.43-1.45 (m, 1H). MS (ESI) m/e [M+1]+ 299.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:40][CH2:41][CH3:42])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:39][C:36]([F:37])([F:38])[O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:43])=[O:5])[C:9]([CH2:40][CH2:41][CH3:42])=[N:10][C:11]=3[CH:16]=2)=[CH:30][CH:31]=1
Reactant: CCCc1nc2cc(N(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(4-Trifluoromethoxy-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.72 (m, 2H), 7.44 (m, 4H), 7.23 (m, 3H), 7.16 (d, 1H), 6.79 (m, 1H), 4.88 (s, 2H), 4.54 (s, 2H), 2.68 (t, 2H), 1.72 (m, 2H), 0.95 (t, 3H). MS calculated for C26H23F4N3O5S—H: 564, observed: 564.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:8]1[C:7]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([Cl:17])[CH:9]=1)(=[O:20])[CH3:19]
Reactant: N#CC1CCNCC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(C#N)CC1
Temperature: 65 °C
Yield: 6.6 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), piperidine-4-carbonitrile (0.045 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The resulting residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (7 mg, 6%). LCMS calculated for C17H17ClN3O (M+H)±: m/z=314.1; Found: 314.0.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[C:64]1([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: Nc1ccccc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 23.5 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.15 g, 0.26 mmol), was reacted with diisopropylethylamine (0.17 g, 1.3 mmol), diphenylphosphinic chloride (0.17 g, 0.53 mmol), then reacted with aniline (Aldrich) (0.05 g, 0.53 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid phenylamide as a white foam (Yield 0.033 g, 24%).
Reaction SMILES: CN.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13](Cl)=[N:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[CH2:28]([N:30](CC)CC)C>O1CCCC1>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]([NH:30][CH3:28])=[N:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(Cl)nc1)C(Cl)=NNc1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40% aqueous solution of methylamine (78 mg, 1.0 mmol) was gradually added to a solution of N-(6-chloro-3-pyridylmethyl)-2-chloro-2-(4-trifluoromethylphenyl hydrazono) acetic acid amide (Compound No. 5) (0.4 g, 1 mmol) and triethylamine (0.1 g, 1 mmol) in tetrahydrofuran (10 ml) and left at room temperature overnight. Further, 40% aqueous solution of methylamine (10 mg, 0.13 mmol) was added and stirred at room temperature for 1 hour, and thereafter subjected to extraction by adding ethyl acetate and water. The organic phase was washed with a saturated brine, and then dried on anhydrous sodium sulfate. The resulting residue was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-methylamino-2-(4-trifluoromethylphenyl hydrazono) acetic acid amide (Compound No. 191) (0.13 g, 0.34 mmol, 34%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[C:15]([F:22])[CH:14]=1.C[O-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)[C:20]=2[NH2:21])=[C:15]([F:22])[CH:14]=1
Reactant: COc1ccc(N=[N+]=[N-])cc1
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(Cl)cc3F)c2N)cc1
Temperature: 0 °C
Yield: 3.3 %

Procedure:
To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (2.000 g, 13.4090 mmol) and commercial (4-chloro-2-fluoro-phenyl)-acetonitrile (2.729 g, 16.0909 mmol) in absolute ethanol (30 ml), an ice-cooled solution of sodium methoxide (1.087 g, 20.1136 mmol) in absolute ethanol (20 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜4.3 g of crude material as brownish solid. This crude product is purified by column chromatography eluting with 25-35% ethyl acetate in hexane, to obtain the title compound as a yellow solid (0.140 g, 3.25% yield). M.p. 147.9-149.5° C. LC-ESI-HRMS of [M+H]+ shows 319.0779 Da. Calc. 319.076192 Da, dev. 5.4 ppm
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([CH2:16][S:17]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[C:34](=[O:35])[CH2:33][C:32](=[O:36])[NH:31][C:30]4[C:37]5[C:42]([CH:43]=[CH:44][C:29]3=4)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:24][CH:23]=2)[CH3:21])(=[O:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11]1)([O-])=O.O.O.[Sn](Cl)Cl>ClCCl.C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([CH2:16][S:17]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[C:34](=[O:35])[CH2:33][C:32](=[O:36])[NH:31][C:30]4[C:37]5[C:42]([CH:43]=[CH:44][C:29]3=4)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:24][CH:23]=2)[CH3:21])(=[O:19])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH2:15]1
Reactant: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)S(=O)(=O)CC1(c2ccccc2[N+](=O)[O-])C=CC=CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)S(=O)(=O)CC1(c2ccccc2N)C=CC=CC1
Temperature: 30 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
1-(2-Nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide (33 mg, 0.062 mmol) mentioned above was dissolved in a mixed solvent of dichloromethane (0.5 mL) and ethyl acetate (1.5 mL), then the solution was added with tin(II) chloride dihydrate (70 mg, 0.310 mmol), and the mixture was stirred at 30° C. for 16 hours. After the disappearance of the starting materials was confirmed, the reaction mixture was treated in a conventional manner to give the title compound (26 mg, yield 31%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[N:37][C:36]=1[C:41](O)=[O:42].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:14]([NH:13][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([NH:1][C:41]([C:36]3[N:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])=[CH:3][C:4]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:16])[CH3:15]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Reactant: O=C(O)c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(NC(=O)c3ncccn3)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Ethyl 1-[5-[7-amino-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (159 mg, 0.27 mmol), pyrimidine-2-carboxylic acid (64.2 mg, 0.52 mmol) and diisopropylethylamine (271 mg, 2.1 mmol) were dissolved in DMF (5 mL). The reaction was purged with N2 then HATU (197 mg, 0.5 2 mmol) was added and the reaction stirred at rt for 18 h. The DMF was removed under reduced pressure and the resulting residue diluted with water and extracted with EtOAc. During the work up a solid precipitated which was collected by filtration and dried in the vacuum oven to provide the crude product (100 mg, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Yield: 82.5 %

Procedure:
A solution of (3,4-dichloro-phenyl)-acetic acid (10.0 g, 0.048 mol) in ethanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 7 h. The reaction was concentrated in vacuo, diluted with diethyl ether, and poured into water. The ether layer was washed with a saturated aqueous sodium bicarbonate solution and water. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. Vacuum distillation (bath temperature: 175° C.; head temperature: 125° C.) afforded (3,4-dichloro-phenyl)-acetic acid ethyl ester (9.38 g, 82.5%) as a clear oil: EI-HRMS m/e calcd for C10H10Cl2O2 (M+) 232.0058, found 232.0066.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[CH3:11]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(F)c1C

Procedure:
3-Fluoro-2-methyl-benzoic acid (4.8 g, 31 mmol), potassium carbonate (4.3 g, 31 mmol) and methyl iodide (4.5 g, 31 mmol) were stirred at room temperature for 17.5 hours in anhydrous N,N-dimethylformamide (50 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic, layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 4.8 g (27 mmol, 87% in yield) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([O:35]C)=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:21])=[O:20])=[O:9])[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([OH:35])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:20])=[O:21])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCC[C@@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 110 °C
Yield: 36.8 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-2-yl)carbonylamino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 146, 0.120 g) and lithium hydroxide monohydrate (0.095 g) was suspended in dioxane (5 mL) and water (1 mL) and the mixture was stirred and heated at 110° C. for 22.5 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-2-yl)carbonylamino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.043 g) as a white solid.
Reaction SMILES: C1(C2N3C=CN=C(N)C3=C(I)[N:6]=2)CCC1.Cl[C:17]1[C:18]2[N:19]([C:23]([CH:27]3[CH2:30][C:29]([F:32])([F:31])[CH2:28]3)=[N:24][C:25]=2[I:26])[CH:20]=[CH:21][N:22]=1>>[F:31][C:29]1([F:32])[CH2:30][CH:27]([C:23]2[N:19]3[CH:20]=[CH:21][N:22]=[C:17]([NH2:6])[C:18]3=[C:25]([I:26])[N:24]=2)[CH2:28]1
Reactant: FC1(F)CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Product: Nc1nccn2c(C3CC(F)(F)C3)nc(I)c12

Procedure:
Prepared according to the procedure described above for 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine, except using 8-chloro-3-(3,3-difluoro-cyclobutyl)-1-iodo-imidazo[1,5-a]pyrazine. HPLC: tR=1.87 min. (Open Lynx polar—5 min). MS (ES+): m/z 350.74 (100) [MH+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Product: CN(C)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 23.2 %

Procedure:
In a similar fashion using route 48 general procedure 114, N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (80 mg, 0.250 mmol) and dimethyl amine (2M in THF; 1.25 ml, 2.50 mmol) gave the title compound (19 mg, 23%) after purification by column chromatography with chloroform/MeOH (1 drop NH3) (98:2) as the eluent followed by recrystallisation from MeOH/DCM.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]5[CH:42]=[CH:41][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccc(C(=O)O)cc6)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and methyl 4-(piperidin-4-yl)benzoate hydrochloride (APAC Pharm. LLC, Cat. No. 875920). LCMS (M+H)+: m/z=528.3.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:12]([O:14]CCO)=[O:13])[NH:10][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[NH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCCO)c1cc(Oc2ccc(Cl)cc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(Oc2ccc(Cl)cc2)c[nH]1
Reaction time: 16 h

Procedure:
2-Hydroxyethyl 4-(4-chlorophenoxy)pyrrole-2-carboxylate (400 mg.) was dissolved in 10 ml. of acetone and 10 ml. of 1N sodium hydroxide and left to stand at room temperature for approximately 16 hours. Acetone was evaporated in vacuo, the aqueous residue was acidified with conc. hydrochloric acid and crystalline product (320 mg.) recovered by filtration. Recrystallization from ether/hexane of 400 mg. of product prepared in this manner afforded purified 4-(4-chlorophenoxy)pyrrole-2-carboxylic acid (234 mg., m.p. 188°-190° C., m/e 237).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12.[OH-].[K+].ClCCl.CO>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCN(C)CC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(-c3cc4c(Cl)ccnc4[nH]3)cn(CCN3CCN(C)CC3)c2cc1OC
Yield: 33.5 %

Procedure:
But using 0.2 g of 4-chloro-2-{5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl}-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.65 g of potassium hydroxide in 7 ml of methanol. After flash chromatography on a silica column [eluent: dichloromethane/methanol (80/20 by volume)], 0.05 g of 4-chloro-2-{5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl}-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows: