Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1cccc(C(F)(F)F)c1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy) acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and 3-trifluoromethylbenzylamine (2.2 eq.) in the manner of example 68, m.p.143-145° C. MS [(+)ESI, m/z]: 554 [M+H]+ Anal. Calcd for C29H23CIF3N3O3: C, 62.88; H, 4.18; N, 7.59. Found: C, 62.87; H, 4.08; N, 7.52.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:14]1CCC(N=C=NC2CCCCC2)C[CH2:15]1>CCO>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([NH2:1])[CH:3]=1)[CH3:15]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc([N+](=O)[O-])c1

Procedure:
3-Amino-5-nitrobenzoic acid (910 mg, 5.0 mmol) was dissolved in EtOH (25 mL). DCC (1.51 g, 7.3 mmol) was added, and the mixture was stirred under reflux overnight. The solid precipitation was filtered off and the filtrate was evaporated. The residue was triturated in the solvent mixture ether:hexane:ethyl acetate, 5:5:1. The title compound was isolated as a fine light yellow powder (0.9 g, 85.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10])(=[O:31])=[O:32]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-5-methylbenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 390 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-methylbenzenesulfonylamino)phenyl]-amide. LC: Tr 1.25 min; MS: 489.1 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][OH:26])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][OH:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([O:20][N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])=[O:19])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)[nH]c1=O

Procedure:
A solution of 45 g. of 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid and 14.0 g. of N-hydroxysuccinimide in 450 ml. of dimethylformamide is cooled to 0°-5° C. and treated dropwise, with stirring, with a solution of 26.8 g. of N,N'-dicyclohexylcarbodiimide in 30 ml. of dimethylformamide. The mixture is stirred for 16 hours at room temperature, then cooled and filtered to remove by-product N,N'-dicyclohexylurea. The filtrate is diluted with 1.5 l. of 2-propanol and the resulting precipitate of 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester is collected by filtration, washed with cold 2-propanol and dried; m.p. 213°-215.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26]([C:27](O)=[O:28])=[CH:25][C:24]([CH3:30])=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[N:22]([CH3:21])[N:23]=[C:24]([CH3:30])[CH:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n(C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1,3-dimethyl-1H-pyrazole-5-carboxylic acid as starting materials, MS (LC/MS): 425.6 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:23]1[S:24][C:25]([CH2:28][N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>C(Cl)(Cl)Cl>[N:33]1[N:29]([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:34])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:27][CH:26]=2)[N:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cn2nccn2)s1
Solvent: ClC(Cl)Cl
Product: O=C(NC(C(=O)O)c1ccc(Cn2nccn2)s1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[5-(1,2,3-triazol-2-ylmethyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester by (Description 59) the procedure described in Example 29. vmax (CHCl3) 3289 and 1621 cm-1. δ (CD3SOCD3) 1.68-1.83 (2H, m), 2.44-2.73 (5H, m), 5.20 (1H, d, J 6.87 Hz), 5.73 (2H, s), 6.83-6.94 (2H, m), 7.10-7.30 (5H, m), 7.74 and 7.78 (2H, two s's), 8.10 (1H, d, J 7.07 Hz). m/z 431 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]#[N:12].C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[NH:12][C:16](=[O:25])[C:17]2[C:18]([CH:24]=1)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2
Reactant: C[C@H]1C[C@H](CO)N(CCC#N)C1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](C)C[C@@H]3CO)cc12

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514–522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9]C)=O)=[N:4][S:5][CH:6]=1.O.[NH2:12][NH2:13]>CO>[CH3:1][C:2]1[C:3]([C:7]([NH:12][NH2:13])=[O:9])=[N:4][S:5][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1nscc1C
Solvent: CO
Solvent: O
Product: Cc1csnc1C(=O)NN
Temperature: 25 °C

Procedure:
Methyl 4-methyl-3-isothiazolecarboxylate (I128) (57 mg, 0.363 mmol) was dissolved in methanol (3 mL), treated with hydrazine hydrate (0.027 mL, 0.544 mmol) then heated at reflux for 18 hours. Cooled to RT then solvent evaporated, azeotroped with Et2O (3 ml), and evaporated to afford a pale yellow solid of desired product in 57 mg.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH2:34](Br)[C:35]#[CH:36]>>[CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:5]([CH2:36][C:35]#[CH:34])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: C#CCBr
Product: C#CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Yield: 103 %

Procedure:
In a manner analogous to that described in Example 45(i), from 5.0 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1,1,2(R)-pentanetricarboxylate and 3.3 g of propargyl bromide there were obtained 5.58 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-yn-1-yl)-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS 493 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N-methyl propargylamine (23.3 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (15.6 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 8 h to give (Z)-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=O)[CH2:34][NH:35][C:36]([CH:38]4[CH2:42][C:41]5([CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]5)[CH2:40][N:39]4[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:67]>O1CCOCC1.C(OCC)(=O)C>[CH3:7][CH:6]([CH3:8])[C@H:5]([NH:4][C:3](=[O:62])[O:2][CH3:1])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[N:67]=[C:36]([CH:38]5[CH2:42][C:41]6([CH2:43][CH2:44][S:45](=[O:49])(=[O:48])[CH2:46][CH2:47]6)[CH2:40][N:39]5[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:53])[CH3:54])[NH:35][CH:34]=4)=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[N:20]=1)=[O:10]
Reactant: [NH4+]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)NCC(=O)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)n3)cc2)cc1)C(C)C
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 110 °C
Yield: 37.9 %

Procedure:
A solution of methyl((1S)-2-methyl-1-{[(2S)-2-(4-{4′-[({[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-8,8-dioxido-8-thia-2-azaspiro[4.5]dec-3-yl]carbonyl}amino)acetyl]-4-biphenylyl}-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}propyl)carbamate (108) (107 mg, 0.12 mmol) and ammonium acetate (94 mg, 1.2 mmol) in dioxane (1.5 mL) was degassed with nitrogen and heated to 110° C. in a sealed tube for 18 h. The reaction was cooled to room temperature and diluted with ethyl acetate and filtered and concentrated in vacuo. Purified by SFC to afford the product as a tan solid (39 mg, 37% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.64 (br. s., 10H) 7.32 (br. s., 2H) 5.05-5.24 (m, 1H) 4.04-4.29 (m, 1H) 3.99 (br. s., 1H) 3.81 (br. s., 1H) 3.55-3.73 (m, 6H) 3.03-3.25 (m, 4H) 1.80-2.47 (m, 14H) 0.68-1.06 (m, 16H). HRMS for C44H57N8O8S (M+H)+ calc: 857.4020. found: 857.4020. Purity (LC-MS): 97%.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][CH:17]([OH:21])[CH2:18][C:19]#[N:20].C(=O)(O)[O-].[Na+]>C(O)C>[C:19]([CH2:18][CH:17]([OH:21])[CH2:16][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: N#CCC(O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(CC(O)CC#N)CC1
Temperature: 90 °C
Reaction time: 19 h
Yield: 66.4 %

Procedure:
To a solution of tert-butyl 1,4-diazepane-1-carboxylate (4.65 g, 23.2 mmol) and 4-chloro-3-hydroxybutanenitrile (2.0 g, 17 mmol) in ethanol (40 mL) was added sodium bicarbonate (2.1 g, 25 mmol). The mixture was stirred at 90° C. for 19 hours. After cooling to room temperature, ethanol was evaporated. The remaining mixture was diluted with ethyl acetate and washed with water and brine. The organic was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column (0% to 10% methanol/DCM) to give the desired product as yellow oil (3.2 g, 68%). LCMS calculated for C14H26N3O3(M+H)+: m/z=284.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=O)[NH:16][N:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]([N:25]=1)=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:15]=[N:16][C:17]=2[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nnc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12

Procedure:
2-Benzyloxy-8-phenyl-6H-pyrido[2,3-d]pridazin-5-one (845 mg) was stirred in phosphorus oxychloride (30 ml) at reflux for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate, yielding 2-benzyloxy-5-chloro-8-phenylpyrido[2,3-d]pyridazine as a pale yellow solid (950 mg). 1H NMR (400 MHz, DMSO) δ5.50 (2H, s), 7.35 (5H, m), 7.58 (3H, m), 7.65 (1H, d, J=9.0 Hz), 8.06 (2H, m), 8.60 (1H, d, J=9.0 Hz); MS (ES+) m/e 348, 350 [MH]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>N1CCCCC1.C(O)C>[O:16]=[C:10]1[C:9](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1[nH]cc2c1CCOC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 4-oxo-2,4,6,7-tetrahydropyrano[3,4-c]pyrrole-1-carbaldehyde (39.2 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 48 hours. The precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give 15 mg (17%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](/[CH:14]=[C:15](\[S:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])/[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[O:17])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:36]I.[H-].[Na+]>CN(C)C=O.O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](/[CH:14]=[C:15](\[S:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])/[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[O:17])=[CH:10][N:11]2[CH3:36])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)/C(=C/c2c[nH]c3cc(NC(C)=O)ccc23)SCC(O)CO)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)/C(=C/c2cn(C)c3cc(NC(C)=O)ccc23)SCC(O)CO)cc(OC)c1OC
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Compound 125 (300.0 mg) obtained in Example 125 was dissolved in a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), and methyl iodide (93.6 mg) and then sodium hydride (26.4 mg, 60% mineral oil dispersion) were added thereto, followed by stirring for 1.5 hours. The reaction solution was subjected to partitioning between chloroform and water, and the organic layer was successively washed with water and a saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude crystals were washed with chloroform and recrystallized from a mixed solvent of ethanol, N,N-dimethylformamide, and water to give Compound 126 (249.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].[OH-].[Na+].Cl>CN1CCCC1=O.O>[CH3:17][O:16][C:14](=[O:15])[CH:13]([C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1])[C:12]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
3-Chloro 4-fluoro nitrobenzene (5.0 g, 28.48 mmol) and dimethyl malonate (3.3 mL, 36.17 mmol) were dissolved in N-methylpyrrolidinone (131.5 mL). Sodium hydroxide (2.4 g, 60 mmol) was added at RT and the solution was heated at 80° C. for 2 hours. The reaction mixture was cooled to 5° C. and 1N HCl solution was added to give a pH of 2. Water (526 mL) was added and the resulting mixture was stirred for 15 minutes during which a pale yellow solid precipitated out. The precipitate was collected by filtration and then washed with water (2×10 mL). The resulting solid mass was dissolved in DCM (50 mL), dried (Na2SO4) and then the volatiles were removed under reduced pressure to afford the title compound (5.5 g, 67%). The product was used as such in the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[C:24]([Cl:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[Cl:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:26][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([Cl:25])[C:15]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cc(Cl)c(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(OCC2CCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3,5-dichlorobenzoate (988 mg, 3.248 mmol) in CH2Cl2 (20 mL) was added TFA (5 mL) at 0° C., and the reaction mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure and the residue was treated with 1 N NaOH. The solution was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 672 mg (68%) methyl 3,5-dichloro-4-(2-pyrrolidinyl)methoxybenzoate as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ 1.62–1.69 (m, 1H), 1.78–1.86 (m, 2H), 1.89–1.99 (m, 1H), 2.92–2.98 (m, 1H), 3.04–3.09 (m, 1H), 3.55–3.60 (m, 1H), 3.91 (s, 3H), 4.01 (dd, J=6.8, 8.8 Hz, 1H), 4.08 (dd, J=4.9, 8.8 Hz, 1H), 7.97 (s, 2H); MS (FAB) m/z 304 (M++1).
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:29]#[N:30])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:31]=[CH:32][CH:33]=[N:34][C:11]2=3)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>CO>[OH:28][CH2:27][CH2:26][N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:31]=[CH:32][CH:33]=[N:34][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:29]#[N:30])[CH2:25][CH2:24]1
Reactant: N#Cc1ncc2c(c1OC1CCN(CCO)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ncc2[nH]c3ncccc3c2c1OC1CCN(CCO)CC1
Yield: 45.6 %

Procedure:
A solution of 9-benzenesulfonyl-5-[1-(2-hydroxyethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (125 mg, 0.26 mmol) and triethylamine (1 mL) in methanol (10 mL) was heated to 60° C. for 3 hours. The mixture was concentrated in-vacuo and the resultant residue purified by flash chromatography (silica, 10 g column, ISCO, 0-8% methanol in dichloromethane). The resultant material was triturated with acetonitrile and methanol to afford the title compound as an off-white solid (40 mg, 45%). LCMS (Method C): RT=4.83 min, M+H+=338.2. 1H NMR (400 MHz, DMSO-d6): 8.79 (s, 1H), 8.70 (dd, J=4.8, 1.6 Hz, 1H), 8.59 (dd, J=7.9, 1.7 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 4.71-4.69 (m, 1H), 4.38 (s, 1H), 3.49 (s, 2H), 2.93-2.81 (m, 2H), 2.40 (t, J=6.3 Hz, 2H), 2.15 (t, J=11.1 Hz, 2H), 2.06 (d, J=12.0 Hz, 2H), 1.93-1.92 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1.[C:20]([C:28]1[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:13]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28]3[C:29](=[CH:33][CH:34]=[C:35]([Br:37])[CH:36]=3)[C:30]2=[O:31])=[CH:9][CH:10]=1
Reactant: CCCC(O)CNCc1ccc(C(=O)OC)cc1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
In the same manner as in Example 458, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzoic acid methyl ester hydrochloride and 2-benzoyl-4-bromobenzoic acid.