Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:27])=[CH:24][C:23]=4[F:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)cc(F)c1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(C)CC2)cc(F)c1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (m, 4 H) 1.58 (d, J=14.4 Hz, 6 H) 1.75 (m, 2 H) 1.93 (m, 2 H) 1.99 (s, 1 H) 2.16 (s, 3 H) 2.78 (d, J=10.6 Hz, 2 H) 3.29 (s, 3 H) 3.83 (s, 2 H) 3.89-4.01 (t, J=12 Hz, 2 H) 4.32 (m, 1 H) 7.24-7.48 (m, 2 H) 8.10 (s, 1 H) 8.26 (d, J=7.6 Hz, 1 H) 8.53 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17][CH2:16]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: c1ccc2c(c1)NCCN2
Product: O=C(CSc1nc2ccccc2s1)N1CCNc2ccccc21
Yield: 51 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 1,2,3,4-tetrahydroquinoxaline to yield 41 as a white solid (51%) MS m/z: 342 (M+H)+. Anal. Calcd. For, C17H15N3OS2.0.2H2O: C, 59.18; H, 4.50; N, 12.18; S, 18.52. Found: C, 59.32; H, 4.65; N, 12.18; S, 18.25.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=S>CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[N:1][NH2:2]
Reactant: NN
Reactant: S=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Solvent: CO
Product: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Reaction time: 24 h
Yield: 126.7 %

Procedure:
Hydrazine (0.32 ml, 10 mmol) was added to a suspension of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbothioamide (90 mg, 0.2 mmol) in 3 ml of methanol and the reaction mixture was stirred for 24 hour. The precipitate was filtered, washed with methanol and dried in vacuum to give N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbohydrazonamide (94 mg, 90%). MS: (ESI+)=371.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](O)=[O:27])=[CH:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:26]([C:19]4[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[NH:17][CH:18]=4)=[O:27])[CH2:14][CH2:15]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: O=C1Nc2ccc(Br)cc2C12CCNCC2
Product: O=C(c1c[nH]c2ccccc12)N1CCC2(CC1)C(=O)Nc1ccc(Br)cc12

Procedure:
Following the general procedure I as described above, the acylation of 5-bromospiro[indole-3,4′-piperidin]-2(1H)-one with 1H-indole-3-carboxylic acid (commercially available), gave the title compound. ES-MS m/e (%): 424.3(M+H+).
Reaction SMILES: CS[C:3]1[C:4]2[NH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:12])[N:11]=1.[NH2:22][NH2:23]>O>[CH2:13]([N:9]1[C:8]2[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[NH:5][C:4]=2/[C:3](=[N:22]\[NH2:23])/[NH:11][C:10]1=[O:12])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCn1c(=O)nc(SC)c2[nH]c(C(F)(F)F)nc21
Reactant: NN
Solvent: O
Product: CCCCCn1c(=O)[nH]/c(=N/N)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C

Procedure:
A mixture of 6-(methylthio)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-2H-purin-2-one (0.15 g, 0.23 mmol) and hydrazine (0.80 mL, 25 mmol) in water (0.80 mL) was heated at 100° C. for 1 h. The solution was concentrated under reduced pressure and azeotropically treated with toluene twice. The resulting residue was used for next step without purification. LCMS calculated for C11H16F3N6O (M+H): 305.1. found: 305.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:2]1.[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C@@H:13]4[CH2:14][CH2:15][C@H:10]([C:3]5[C:4]6[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=6)[NH:1][CH:2]=5)[CH2:11][CH2:12]4)[CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1cc(N2CCN([C@H]3CC[C@@H](c4c[nH]c5ccccc54)CC3)CC2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(1H-indol-3-yl)-cyclohexanone (0.53 g, 2.5 mmol), 1-(indol-4-yl)piperazine (0.5 g, 2.5 mmol), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in 1,2-dichloroethane (11 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml), and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.52 g (53%) of product as a white solid: mp 85-87° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][O:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Oc1ncccn1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)COc3ncccn3)C(=O)O)cc2)cc1

Procedure:
Example 56 is prepared from 2-hydroxypyrimidine and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][C:2]1([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CCN(CC)CC.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][C:2]1([N:5]2[CH2:10][CH2:9][N:8]([S:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:18])([F:30])[F:31])(=[O:28])=[O:27])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC1(N2CCNCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(N2CCN(S(=O)(=O)c3ccccc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
1-(1-Methylcyclopropyl)piperazine (TFA salt) (50.9 mg, 0.200 mmol) was dissolved in dichloromethane (1.0 mL) and NEt3 (0.3 mL) was added. To this mixture, 2-trifluoromethylbenzenesulfonyl chloride (73.4 mg, 0.300 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo and the resulting crude mixture was purified by HPLC (25-40% acetonitrile in water (0.05 TFA buffer). The product containing fractions were concentrated in vacuo until only water was left, basified with NaHCO3 (sat. aq., 20 mL) and extracted with dichloromethane (3×7 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a white solid (56.6 mg, 81%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.28-0.32 (m, 2 H), 0.39-0.44 (m, 2 H), 0.98 (s, 3 H), 2.59 (t, J=4.80 Hz, 4 H), 3.08 (m, 4 H), 7.84-7.93 (m, 2 H), 7.99-8.04 (m, 2 H); ESI-MS: m/z 349.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:11])[C:4]([CH3:10])=[CH:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH:15]=[O:16].Cl>C(#N)C.O>[OH:16][CH:15]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([OH:11])=[C:4]([CH3:10])[CH:5]=1)[CH:14]([O:17][CH3:18])[O:13][CH3:12]
Reactant: Cc1ccc(C)c(O)c1
Reactant: COC(C=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(OC)C(O)c1cc(C)c(O)cc1C
Yield: 81 %

Procedure:
A suspension of an aqueous solution of 5.2% sodium hydroxide (630 g), 2,5-xylenol (100 g), an aqueous solution of 60% glyoxal dimethyacetal (213 g) and water (200 g) was heated at 55° C. for 5 hours with stirring. The reaction mixture was cooled in an ice bath, and to the mixture were added acetonitrile (90 g) and 7.4% hydrochloric acid (380 g) successively. The precipitating crystals were filtered to give 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (150 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COCCN
Reactant: CCOc1cc(Br)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Product: CCOc1cc(NCCOC)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 31 %

Procedure:
The same reaction procedure as in Example 27 was performed, except that the compound obtained in Example 85 was used in place of the compound obtained in Example 26, and 2-methoxyethylamine was used in place of N-methylpiperazine. In this manner, 46 mg (31%) of the captioned compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]Cl)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)C>[C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][O:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CCl)ccc21
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1ccc2cc(COC3CCCCC3)ccc21
Temperature: 35 °C
Yield: 28 %

Procedure:
A mixture of 5-chloromethyl-indole-1-carboxylic acid tert-butyl ester (0.41 g, 1.55 mmol, 1.0 eq.), cyclohexanol (0.82 mL, 5.0 eq.) and Ag2O (1.80 g, 5.0 eq.) in diethyl ether (5 mL) was stirred at 35° C. over weekend. After cooling to room temperature, the reaction mixture was filtered through celite washing with ether. The filtrate was concentrated and the residue was purified by chromatography (3% EtOAc/hexanes) to give N-Boc-5-cyclohexyloxymethylindole (160 mg, 28%) as colorless oil. 1HNMR comfirmed the compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37][S:38]([C:41]3[CH:46]=[CH:45][C:44](I)=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:64][C:65](C1C=CC=CC=1S(Cl)(=O)=O)=[O:66])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>O1CCOCC1>[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:65]([O:64][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:66])(=[O:40])=[O:39])[CH2:27][O:28][C:29]3[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=3)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccc(I)cc2)c1
Reactant: O=C(OCc1ccccc1)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 ml of 4 N hydrogen chloride in dioxane and 2.5 ml of dioxane were added to 500 mg (0.854 mmol) of 3-[(2S)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]-2-(4-iodobenzenesulfonylamino)propoxy]benzonitrile. The mixture was stirred at room temperature for 24 hours, and the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 8 ml of DMF, and 0.49 ml (2.56 mmol) of di-isopropylethylamine and 398 mg (1.28 mmol) of 2-(benzyloxycarbonyl)benzene sulfonyl chloride were added thereto at 0° C. The mixture was stirred for 1 hour, then allowed to reach room temperature, and stirred for additional 24 hours. The reaction solution was extracted with ethyl acetate, washed with water, 1 N hydrogen chloride and saturated saline, and dried over powdery magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:21]([NH2:24])[CH:22]=[CH2:23].C(=O)([O-])O.[Na+]>>[CH2:21]([NH:24][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:8]=1)[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2c(-c3ccccc3)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(-c3ccccc3)c2n1
Yield: 85.3 %

Procedure:
168 mg (0.56 mmol) of 4-allylamino-2-chloro-7-phenylthieno[3,2-d]pyrimidine and 508 mg (8.9 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (30 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 154 mg (yield: 85.3%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([CH2:9][C:10]#[C:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2)[C:5]([O:7]C)=[O:6].O[Li].O>C1COCC1.O>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][NH:24][C:23]=1/[CH:22]=[C:14]1\[C:15](=[O:21])[NH:16][C:17]2[C:13]\1=[C:12]([C:11]#[C:10][CH2:9][CH:4]([C:3]([OH:30])=[O:2])[C:5]([OH:7])=[O:6])[CH:20]=[CH:19][CH:18]=2
Reactant: COC(=O)C(CC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCC(C(=O)O)C(=O)O)c21

Procedure:
Using Method F above, (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]propanedioic acid dimethyl ester (68 mg, 0.16 mmol) (from Example 26 above) was hydrolyzed with LiOH•H2O (140 mg, 3.32 mmol) in THF (1 mL) and water (1 mL) at room temperature for 20 h to yield (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]propanedioic acid. (Yield 49 mg, 82%).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[N:30]3)=[CH:24][CH:23]=2)[C:9]([NH:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2([C:19]([O-:21])=[O:20])[CH2:18][CH2:17]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>C1COCC1.C(O)C>[CH:3]1([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]3[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[N:30]3)=[CH:26][CH:27]=2)[C:9]([NH:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(NCC/C=C/C1(C(=O)[O-])CC1)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCC=CC1(C(=O)O)CC1)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
86 mg (2.15 mmol) of sodium hydroxide were added to a solution of 120 mg (0.215 mmol) of ethyl cis/trans-1-[4-{[(+)-2-cyclopentyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl]amino}but-1-en-1-yl]cyclopropanecarboxylate in 0.23 ml of THF and 0.56 ml of ethanol. The suspension was stirred at RT for 20 min and then acidified slightly with 1 N hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. This gave 112 mg of the target compound as a cis/trans isomer mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:21])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To the suspension of 2-nitrobenzoic acid (200 g) and a catalytic amount of dimethylformamide (DMF; 5 mL) in DCM (2.5 L) was added oxalyl dichloride (304 g) dropwise at room temperature over a 30 minute interval. After the addition, the reaction was continued stirring for approximately 1 hour at room temperature and the suspension turned into a clear solution. The completion of the reaction was monitored by TLC (generally ˜1 hour). The reaction mixture was then concentrated at 35° C. to dryness to give 225 g of the crude product (13) as light yellow oil or solid (mp: 17° C., lit), which was directly used for the next step without further purification.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 4-methylbenzaldehyde (0.5 g, 4.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.10 g, 81%).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][CH2:24][CH2:25]O)(=[O:16])=[O:15])=[C:9]([CH3:27])[CH:8]=1.O>CN(C=O)C>[Br:2][CH2:25][CH2:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][CH3:5])=[CH:8][C:9]=1[CH3:27])(=[O:16])=[O:15]
Reactant: BrP(Br)Br
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCBr)c(C)c1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
PBr3 (2.64 mmol, 1.5 eq) was added to a solution of 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propan-1-ol (1.76 mmol, 1 eq) in DMF (6 ml) at 0° C. and the mixture was stirred for 30 min. Water (20 ml) was subsequently added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel). Yield: 25%
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:20][C:21]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:27]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Br:20])[CH:28]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)c1cccc2[nH]c3ccccc3c12
Reactant: N#Cc1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
In a 250 ml round-bottomed flask under argon, 391 mg of a suspension of sodium hydride at 60% in petroleum jelly are added at ambient temperature, in 4 stages, in ½ hour, to a solution of 2.0 g of 9H-carbazole-4-carboxylic acid methyl ester obtained according to the preceding stage and of 1.95 g of 2-bromo-4-fluorobenzonitrile in 50 ml of dimethylformamide. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and cyclohexane (50:50). 3.2 g of 9-(3-bromo-4-cyanophenyl)-9H-carbazole-4-carboxylic acid methyl ester are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13](=[N:16][C:17]#[N:18])SC)[N:3]=1.[CH3:19][NH2:20]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:20][CH3:19])=[N:16][C:17]#[N:18])[N:3]=1
Reactant: CSC(=NC#N)NCCSCc1nccc(N)n1
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nccc(N)n1
Reaction time: 18 h

Procedure:
A solution of 4-amino-2-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]pyrimidine (0.75 g.) in 33% w/v methylamine in ethanol (15 ml.) was left at room temperature for 18 hours. The solution was concentrated to 5 ml., cooled in ice, and the crystalline precipitate collected to give 4-amino-2-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyrimidine (0.52 g.), m.p. 189°-190°.