Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[C:17]([CH3:22])=[N:18][N:19]([CH3:21])[CH:20]=1>CO.C1COCC1.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:15][C:16]1[C:17]([CH3:22])=[N:18][N:19]([CH3:21])[CH:20]=1
Reactant: Cc1nn(C)cc1Nc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(C)cc1Nc1c(N)cnc2ccc(Br)cc12

Procedure:
(6-Bromo-3-nitro-quinolin-4-yl)-(1,3-dimethyl-1H-pyrazol-4-yl)-amine (Stage A.3, 3.67 g 9.73 mmol) was shacked in MeOH/THF 1:1 (120 ml) under 1.1 bar H2 in presence of Raney nickel (1.50 g) as catalyst for 5 h at rt. The RM was filtered over celite, the catalyst was washed with MeOH/DCM and the solution was evaporated to dryness to give the title compound as a red solid (HPLC tR 2.44 min (Method A); M+H=334; M−H=332 MS-ES)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:31]1N=C(CC)C(NC2C3C(=CC=CC=3)CCC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:31][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCCc3ccccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.40, 7.32, 7.20, 7.08, 5.41, 4.57, 2.80, 2.53, 2.41, 2.06, 1.96, 1.90, 1.18; 13C NMR (100 MHz, CDCl3) δ 151.50, 150.93, 140.37, 138.53, 138.37, 137.87, 137.123, 135.36, 134.43, 132.95, 129.78, 129.62, 129.44, 127.57, 127.51, 125.63, 60.82, 49.01, 29.96, 27.62, 26.93, 14.61, 13.32, 11.67; HRMS (FAB) calcd for C18H22BrN3+H 360.1076, found 360.1065.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:13][C:14](OCC)=O)[C:5](=O)[NH:6]2>CC(O)=O>[F:11][C:9]1[CH:8]=[C:7]2[N:6]=[CH:5][CH:4]3[CH:13]=[CH:14][NH:1][C:2]([CH:10]=1)=[C:3]23
Reactant: CCOC(=O)CC1C(=O)Nc2cc(F)cc(N)c21
Solvent: CC(=O)O
Product: Fc1cc2c3c(c1)NC=CC3C=N2
Temperature: 25 °C

Procedure:
A solution of (±)-ethyl (4-amino-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step D (3.28 g, 13.0 mmol) in degassed xylenes (100 mL) and AcOH (5 mL) was heated at reflux for 4.5 days, then allowed to slowly cool to ambient temperature. The resulting precipitate was filtered, washing with hexanes, to give the title compound. MS: m/z=207 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=3)[N:8]=[N:7][C:6]=2[C:21](O)=[O:22])[CH2:3][CH2:2]1.C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:6]2[N:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=3)[C:5]=2[CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:22])[CH2:29][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 183.8 %

Procedure:
5-(Cyclopropylmethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (503 mg, 1.60 mmol) obtained in Example 96b), HOBt (109 mg, 0.800 mmol, 0.5 eq.) and cyclopropylamine (0.149 ml, 2.08 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8 ml), WSC (376 mg, 1.92 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (3:1, 40 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (518 mg, 1.47 mmol, 91.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)[C:5]2=[O:33].[CH3:34]OC1C=C2C(=CC=1OC)N=CN=C2N1CCC(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)NC2=O)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:34])[C:7](=[O:12])[N:6]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]1)[C:5]2=[O:33]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(Cl)cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(Cl)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 65 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.64 mmol) of 6-chloro-3-[1(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound h) obtained according to the method described in the literature [Chem. Pharm. Bull., 38, 1591-1595 (1990)] was used in place of Compound 24. As a result, 199.2 mg (yield: 65%) of Compound 40 was obtained as white crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]2[C@H:19]3[C@H:24]([CH2:25][CH2:26][C:17]=2[CH:16]=1)[NH:23][CH2:22][CH2:21][CH2:20]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@H:19]([C:18]5[CH:27]=[CH:28][C:15]([O:14][CH3:13])=[CH:16][C:17]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Product: COc1ccc2c(c1)CC[C@H]1[C@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 71 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 71% of theory; LC (method 1): tR=2.61 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: OC1C=C(N2C3C(=NC=CC=3)N=C2)SC=1C(OC)=O.[OH:20][C:21]1[CH:25]=[C:24]([N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[CH:27]2)[S:23][C:22]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([F:56])([F:55])[F:54]>CN(C)C=O>[N:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:26]([C:24]2[S:23][C:22]([C:35]([O:37][CH3:38])=[O:36])=[C:21]([O:20][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]([F:54])([F:55])[F:56])[CH:25]=2)[CH:27]=1
Reactant: COC(=O)c1sc(-n2cnc3cccnc32)cc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: COC(=O)c1sc(-n2cnc3ncccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cccnc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 12.49 g of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-b]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-b]pyridin-3-yl)thiophene-2-carboxylate (example C8) and 7.45 g of K2CO3 and 12.91 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene in 200 ml N,N-dimethylformamide yield compound B5a and compound B5b.
Reaction SMILES: B.[CH2:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][N:9]=1)[CH3:3].Cl>O1CCCC1>[CH2:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][N:9]=1)[CH3:3]
Reactant: CCOCCOc1ccc(C(=O)O)cn1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCOCCOc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 ml of a 1M solution of borane in tetrahydrofuran are added dropwise at 0° C. to a solution of 2.11 g (10 mmol) of 6-(2-ethoxyethoxy)-nicotinic acid in 40 ml of abs. tetrahydrofuran. The mixture is stirred at room temperature for 3 hours and then acidified with concentrated hydrochloric acid, while cooling, then stirred for 30 minutes and evaporated to dryness. The residue is partitioned between ethyl acetate and saturated sodium carbonate solution, and the aqueous phase is extracted once more with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulphate and evaporated. The residue crystallizes on trituration with pentane.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([CH:23]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[N:24]1[CH:27]([O:28][C:29](=[O:31])[CH3:30])[CH:26]([CH:32]([OH:34])[CH3:33])[C:25]1=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CC(C)=O.O>[CH2:36]([CH:23]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[N:24]1[CH:27]([O:28][C:29](=[O:31])[CH3:30])[CH:26]([C:32](=[O:34])[CH3:33])[C:25]1=[O:35])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)O)C2OC(C)=O)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)=O)C2OC(C)=O)cc1
Reaction time: 0.17 h

Procedure:
Jones' reagent (~1 ml) was added dropwise at room temperature to a solution of 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-acetoxy-2-azetidinone (0.40 g) in acetone (5 ml), followed by stirring for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 1-(di-p-anisylmethyl)-3-acetyl-4-acetoxy-2-azetidinone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:51]=[CH:50][CH:49]=[CH:48][C:10]=1[CH2:11][C:12]1[C:13]([O:24][C@@H:25]2[O:42][C@H:41]([CH2:43][O:44]C(=O)C)[C@@H:36]([O:37]C(=O)C)[C@H:31]([O:32]C(=O)C)[C@H:26]2[O:27]C(=O)C)=[N:14][NH:15][C:16]=1[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:51]=[CH:50][CH:49]=[CH:48][C:10]=1[CH2:11][C:12]1[C:13]([O:24][C@@H:25]2[O:42][C@H:41]([CH2:43][OH:44])[C@@H:36]([OH:37])[C@H:31]([OH:32])[C@H:26]2[OH:27])=[N:14][NH:15][C:16]=1[C:17]([F:23])([F:22])[C:18]([F:19])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-1,2-dihydropyrazol-3-one (55 mg) and acetobromo-α-D-glucose (63 mg) in acetonitrile (2 mL) was added potassium carbonate (23 mg), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1-ethyl acetate) to give 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 50 μL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (33 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([CH2:23][CH2:24][CH2:25][NH2:26])=[CH:21][CH:22]=1)=[O:17].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CCOC(C)=O>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([CH2:23][CH2:24][CH2:25][NH:26][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)=[CH:21][CH:22]=1)=[O:17]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(CCCN)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1ccc(CNCCCc2ccc(C(=O)OC)s2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
A mixture of 4-butylbenzaldehyde (250 mg, 1.541 mmol), 5-(3-amino-propyl)-thiophene-2-carboxylic Acid methyl ester hydrochloride (403 mg, 1.695 mmol), and Na2SO4 (2.189 9, 15.41 mmol) in MeOH (10 mL) was heated at reflux for 4.5 h and additional Na2SO4 (2.19 g) was added. The reaction was heated at reflux for 1 h and was cooled to room temperature. The solids were filtered off with the aid of MeOH and the volatiles were removed in vacuo. The residue was dissolved in THF (10 mL) and CH2Cl2 (10 mL) and the solution was cooled to 0° C. Acetic Acid (185 mg, 3.082 mmol) was added followed by sodium triacetoxyborohydride (653 mg, 3.082 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was diluted with EtOAc and the organic solution was washed with aqueous NaHCO3 followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (99:1 CHCl3:MeOH to 97.5:2.5 CHCl3:MeOH) provided the title compound (309 mg). MS 346 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cn1ccc2c(N)cccc21
Solvent: c1ccncc1
Product: COC(=O)Cn1ccc2c(NS(C)(=O)=O)cccc21
Yield: 71 %

Procedure:
To a solution of crude methyl 2-(4-amino-1H-indol-1-yl)acetate (obtained as reported in Example 15, Step 2, theoretical amount 3.08 mmol) in pyridine (10 ml), methanesulfonyl chloride (464 μl, 5.95 mmol) was added, and the mixture was reacted overnight at room temperature. The solvent was evaporated, and the residue was partitioned between 1N HCl (10 ml) and ethyl acetate (20 ml); the aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic layers were dried over sodium sulfate. After evaporation of the solvent, crude methyl 2-(4-(methylsulfonamido)-1H-indol-1-yl)acetate was obtained and used in the next step without any additional purification (620 mg, 2.196 mmol, 71% yield over 3 steps). MS/ESI+ 283.1 [MH]+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].[Cl:35][C:36]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:37]=1[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[Cl:35][C:36]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:37]=1[CH2:38][N:39]1[CH2:40][CH2:41][N:42]([C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]2=[O:13])[CH2:43][CH2:44]1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C

Procedure:
A mixture of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and 1-(2,4-dichlorobenzyl)piperazine (0.046 g, 0.186 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.20-7.39 (m, 13H), 4.19 (s, 2H), 3.59 (t, J=4.8 Hz, 2H), 3.53 (s, 2H), 3.52 (t, J=6.4 Hz, 2H), 3.42 (t, J=4.9 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H), 2.43 (t, J=4.9 Hz, 2H), 2.32 (t, J=4.9 Hz, 2H); MS (ESI+) m/z 522 (M+H)+.
Reaction SMILES: [Al]([NH2:4])(C)C.C1C=CC=CC=1.C(O[C:14](=[O:41])[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([S:35][CH3:36])=[C:22]2[CH2:37][C:38]([NH2:40])=[O:39])C.Cl>C1C=CC=CC=1>[NH2:4][C:20]1[C:19]([O:18][CH2:17][CH2:16][CH2:15][CH:14]=[O:41])=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]([CH2:37][C:38]([NH2:40])=[O:39])=[C:23]([S:35][CH3:36])[N:24]2[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Reactant: C[Al](C)N
Agent: Cl
Solvent: c1ccccc1
Product: CSc1c(CC(N)=O)c2c(N)c(OCCCC=O)ccc2n1Cc1ccccc1
Temperature: 50 °C
Yield: 84 %

Procedure:
Ten mL of 0.6M (CH3)2AlNH2 /benzene was added to 200 mg (0.45 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methylthio-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester (Example 46) in 25 mL of benzene and the mixture heated at 50° C. for 1.75 hours. After cooling the mixture was decomposed with ice and 1N HCl added. The mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was crystallized from EtOH/CH2Cl2 to give 155 mg (84% yield) of 5-(4-amino-4-oxobutoxyl-2-(methylthio)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 185° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14]Br)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH2:34]([NH:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH:35]([CH3:37])[CH3:36]>C(#N)C>[F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14][N:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCBr)nc2cc(C(F)(F)F)ccn12
Reactant: CC(C)CNCC(C)C
Solvent: CC#N
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCN(CC(C)C)CC(C)C)nc2cc(C(F)(F)F)ccn12
Temperature: 80 °C
Yield: 93.9 %

Procedure:
To a solution of compound 17-H (0.004 g, 0.007 mmol) in acetonitrile (0.4 mL) was added diisobutylamine (0.009 g, 0.071 mmol) and the reaction mixture was heated at 80° C. for 18 h. The solvent was removed in vacuo and the resulting residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 106 as a white solid (0.004 g, 97%); MS m/z (M+H+) 609.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1>CCO.[NH4+].[OH-].[Ni]>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[N:3][C:4]([CH2:20][NH2:21])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cnc(CN)c(-c3ccccc3)c2c1
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile (150 mg) in 20 mL absolute EtOH and 5 ml aqueous NH4OH was added 150 mg of Raney Ni. The reaction was shaken under 12 (40 psi) for 18 h. Filtration and concentration of the reaction gave 85 mg of 1-(6-methoxy-4-phenylisoquinolin-3-yl)methanamine.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:34]([CH2:35]CO)=[C:33]([Si:38]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40])[NH:32][C:29]2=[N:30][CH:31]=1>C1COCC1>[Br:5][CH2:1][CH2:35][C:34]1[C:28]2[C:29](=[N:30][CH:31]=[C:26]([Cl:25])[CH:27]=2)[NH:32][C:33]=1[Si:38]([CH2:39][CH3:40])([CH2:43][CH3:44])[CH2:41][CH3:42]
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
Carbon tetrabromide (3.27 g, 9.65 mmol) was added to a solution of triphenylphosphine (2.56 g; 9.65 mmol) in THF (30 mL). The mixture was stirred at room temperature for 30 minutes. To this green suspension was added a solution of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (2 g; 6.43 mmol) in THF (20 mL) and the resulting reaction mixture was stirred for 20 hours. The precipitate was eliminated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (eluent 5 to 40% ethyl acetate in heptane) to give 1.08 g (45%) of 3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:8][C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH3:7])=[CH:4][C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:17]3[CH:18]=[CH:19][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[NH:8][CH:6]([C:5]4[S:1][C:2]5[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=5[CH:4]=4)[CH3:7])=[CH:15][CH:16]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc2ccccc2s1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4cc5ccccc5s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (1-benzo[b]thiophen-2-yl-ethyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C)cc1-n1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2'-Hydroxy-5-methylphenyl)2H-benzotriazole(Tinuvin P manufactured by Ciba Geigy Co., Ltd., λmax=336 nm) 1.13 part and triethylamine 0.61 part were dissolved in acetonitrile 20 parts. A solution of acetyl chloride 0.43 part/acetonitrile 10 parts was dropped thereto while cooling with ice. After stirring at a room temperature for further 4 hours, the solution was poured into water 200 parts and extracted with chloroform, followed by condensing and refining with recrystallization (isopropyl alcohol/chloroform). A pale yellow crystal 0.9 part of 2-(2'-acetoxy-5-methylphenyl)2H-benzotriazole was obtained. (λmax=298 nm).