Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)=O.S(=O)(=O)(O)[OH:37].OO.[OH-].[Na+]>CO.O>[OH:37][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 15.5 %

Procedure:
Step 3 A suspension of 7-formyl-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (30 mg, 0.052 mmol) in methanol (1 mL) was treated with sulfuric acid (4.2 mL, 0.078 mmol) followed by 30% aqueous hydrogen peroxide (0.032 mL, 0.313 mmol), and stirred at rt for 23 h, The mixture was treated with 1 M aqueous sodium hydroxide (200 mL) and stirred for 1 h. The mixture was diluted with water and the precipitate was collected by filtration, washed with water and dried. The residue was purified by preparative HPLC to provide 7-hydroxy-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a tan powder (3.6 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.90 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=7.9 Hz), 7.65-7.76 (2H, m), 7.48-7.63 (3H, m), 7.42 (1H, d, J=6.6 Hz), 7.03 (1H, d, J=7.9 Hz), 6.98 (1H, s), 6.92 (1H, d, J=8.8 Hz), 6.54 (1H, d, J=9.0 Hz), 4.97 (2H, s), 1.94 (3H, s). Mass spectrum m/z 448.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26]C)=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1.[OH-].[K+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:26])=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide (15 g) was added to a warm solution of 7.5 g of potassium hydroxide in 7.5 ml of water and 60 ml of ethanol. The mixture was stirred at room temperature overnight and then poured into dilute hydrochloric acid. The solid was filtered, washed with water and dried to afford 12.5 g of the desired product: m.p. 155°-157° C. IR (cm-1) 3000, 1720.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: NCC(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(Cl)c4)c4cccc(Cl)c4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(3-chlorophenyl)ethanamine (J. Med. Chem., 1988, 31(7), 1282) using a similar method to that of Preparation 64.
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=N1.N1C=CC=CC=1.[C:19](OCC)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[CH3:20][C:19]1[O:21][C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=1
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Reactant: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nnc(-c2ccc(Br)cn2)o1
Reaction time: 3 h
Yield: 80 %

Procedure:
In 130 ml of acetic anhydride was dissolved 8.6 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6. And then the solution was added with 15 ml of pyridine and stirred for 3 hours for reaction. The reaction mixture was added with ethyl acetate and extracted to separate organic layer. And then the organic layer was washed with water and brine. The organic layer was dehydrated, filtrated and concentrated in vacuo to give 7.3 g of the title compound. Yield 80%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CC([O-])(C)C.[K+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][N:38]4[CH2:39][CH2:40][N:35]([C:30]5[N:29]=[CH:34][CH:33]=[CH:32][N:31]=5)[CH2:36][CH2:37]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1cnc(N2CCN(CC3CC(c4ccc(CN5CCCC5)cc4)C3)CC2)nc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a stirring solution of toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester (159.9 mg, 0.40 mmol) prepared above (Example 4, General Procedure A, Step G) in 2 mL of THF was added 1-(2-pyrimidyl)piperizine (136.2 mg, 0.8 mmol) followed by a solution of KOtBu (136 uL, 0.8 mmol, 1M THF). The reaction was heated to 70 □C (oil bath). After 1 hour DMF (1 mL) was added along with K2CO3 (2 eq). The reaction was then heated to 100 □C. After 3 hours the reaction was cooled to rt and concentrated under reduced pressure. The resulting mixture was diluted with CH2Cl2, quenched with a saturated aqueous solution of NaHCO3. The two layers were separated and the aqueous layer was back extracted with 3:1 chloroform:isopropyl alcohol. The combined organic layers were dried over MgSO4, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 10 g ISCO column, eluting with a gradient of 5%, 10%, 20% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (70.0 mg, 44%) as a colorless oil, and a mixture of cis:trans isomers. The bis-HCl salt was generated by dissolving the title compound in EtOAc and then a solution of HCl (2 eq, 1M HCl, THF) was added. The colorless solid was collected and dried under reduced pressure.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:7]1([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]1=[O:16])[CH2:6]2.[O:21]=[C:22]1[N:26]2[CH2:27][C:28](=[O:34])[NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[C:24]([C:25]=32)[N:23]1[CH2:35][C:36]([OH:38])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:21]=[C:22]1[N:26]2[CH2:27][C:28](=[O:34])[NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[C:24]([C:25]=32)[N:23]1[CH2:35][C:36]([N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:7]1([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]1=[O:16])[CH2:6]2)=[O:38]
Reactant: O=C(O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reactant: CNc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of 5-(methylamino)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, enantiomer B (14 mg, 0.053 mmol, described in Intermediate 19), (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetic acid (14 mg, 0.058 mmol, described in Intermediate 9), PyBOP (41 mg, 0.079 mmol), and N,N-diisopropylethylamine (0.028 mL, 0.158 mmol) was stirred in DMF (1 mL) at 50° C. for 20 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and lyophilized to give the title compound. MS: m/z=495 (M+1). HRMS: m/z=495.1778; calculated m/z=495.1776 for C27H23N5O4.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:35][CH2:34][C@@H:33]([OH:36])[CH2:32]1>>[N:25]1([C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:31]5[CH2:35][CH2:34][C@@H:33]([OH:36])[CH2:32]5)=[CH:12][C:11]=4[CH:13]=3)=[CH:22][CH:21]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O[C@@H]1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CC[C@@H](O)C4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and 3-(R)-pyrrolidinol were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.55 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.78 (s, 1H), 3.35-3.8 (m, 17H), 2.3-2.4 (m, 2H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[O-:26][C:27]#[N:28].[K+]>C(O)(=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:24][C:27]([NH2:28])=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CNC(N)=O)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedures for 542, C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 was reacted with potassium cyanate in acetic acid and water to give 524. MS(ESI+) 399.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.2 Hz, 1H), 7.07 (dd, J=8.2, 1.3 Hz, 1H), 6.95 (br, 1H), 6.44 (t, J=6.1 Hz, 1H), 5.83-5.68 (m, 1H), 5.54 (s, 2H), 4.35 (t, J=5.0 Hz, 2H), 4.18 (d, J=6.1 Hz, 2H), 3.42 (t, J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19](=[O:23])[NH:20]2)=[CH:15][CH:14]=1.Cl.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O>[CH:29]1[CH:28]=[C:27]([N:33]2[CH2:38][CH2:37][N:36]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]4[CH2:17][CH2:18][C:19](=[O:23])[NH:20][C:21]=4[CH:22]=3)[CH2:35][CH2:34]2)[C:26]([Cl:25])=[C:31]([Cl:32])[CH:30]=1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Temperature: 92.5 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
In 600 ml of water was dissolved 36.0 g of potassium carbonate, to which were added 60.0 g of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril and 69.6 g of 1-(2,3-dichlorophenyl)piperazine monohydrochloride. The mixture was heated with stirring at 90 to 95° C. for about 4 hours. Then, the reaction mixture was cooled to about 40° C., and the deposited crystals were collected by filtration. The crystals thus obtained were washed with 240 ml of water and dissolved in 900 ml of ethyl acetate, and an azeotropic mixture of water/ethyl acetate (about 300 ml) was distilled out under reflux. The remaining solution was cooled to 0 to 5° C., and the deposited crystals were collected by filtration. The crystals thus obtained were washed with 120 ml of ethyl acetate and dried under a reduced pressure of 50 Torr, at 50 to 60° C. for 3 hours to obtain 98.4 g of aripiprazole (yield 92.8%, purity 99%). mp. 140° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][C@H:33]([CH3:36])[C@H:32]([NH2:37])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:37][C@H:32]4[C@@H:33]([CH3:36])[CH2:34][CH2:35][N:30]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:31]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: C[C@H]1CCN(Cc2ccccc2)C[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CCN(Cc2ccccc2)C[C@H]1Nc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 88.5 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (692 mg, 2.10 mmol), racemic cis 1-benzyl-4-methyl-piperidin-3-ylamine (460 mg, 2.30 mmol) and diisopropylethylamine (1.25 mL, 7.20 mmol) in propan-2-ol (30 mL) was heated to reflux for 2 hours. The cooled reaction mixture was filtered and the yellow solid dried under vacuum to afford 940 mg (90%) of racemic cis (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(1-benzyl-4-methyl-piperidin-3-yl)-amine. LCMS (Method H, ESI): RT=2.61 min, m+H=506.2; 1H NMR (400 MHz, DMSO) δ: 9.67 (d, 1H), 8.94 (s, 1H), 8.13 (dd, 2H), 7.75 (m, 2H), 7.66 (m, 2H), 7.30-7.10 (m, 6H), 4.54 (d, 1H), 3.49 (m, 2H) 2.83 (t, 2H), 2.27 (d, 1H), 2.07 (m, 1H), 1.91 (br s, 1H), 1.47 (m, 2H), 0.81 (d, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (R)-tert-butyl piperidin-3-ylcarbamate (10.00 g, 49.93 mmol) and triethylamine (20.88 mL, 149.8 mmol) in CH2Cl2 (100 mL) at 0° C. (ice bath) was treated dropwise with benzyl carbonochloridate (10.54 mL, 74.90 mmol) and stirred at 0° C. After 2 hours, the mixture was diluted with CH2Cl2 (50 mL) and successively washed with ice cold 10% HCl (2×30 mL), water (1×30 mL), saturated NaHCO3 (1×30 mL), and brine (1×30 mL) The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 60) eluting with 20% EtOAc/hexane (3 L). The fractions containing the product were pooled, concentrated in vacuo and dried under high vacuum for 18 hours to provide (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate as a solid. LCMS (APCI+) m/z 335 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CS(=O)(=O)CCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccn1
Yield: 65 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. Yield: 65% of theory, C31H35N7O7S (649.7) Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1) ##EQU74##
Reaction SMILES: COC1C=C(N[CH2:12][C:13]2[CH:36]=[CH:35][C:16]([C:17]([NH:19][C:20]3[CH:25]=[C:24]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=[CH:22][C:21]=3[NH2:34])=[O:18])=[CH:15][CH:14]=2)C=CC=1OC>CO.C(OCC)(=O)C.[Pd]>[NH2:34][C:21]1[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][C:20]=1[NH:19][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[CH:36][CH:35]=1
Reactant: COc1ccc(NCc2ccc(C(=O)Nc3cc(C=Cc4ccccc4)ccc3N)cc2)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cc(CCc3ccccc3)ccc2N)cc1
Reaction time: 1 h

Procedure:
To a degassed solution of compound 127 (100 mg, 0.209 mmol) in a mixture of methanol and ethyl acetate (1:1) was added was added a catalytic amount of 10% palladium on charcoal and the mixture was put under H2 atmosphere (latm) and stirred for 1 h and filtered through celite and the filtrate was concentrated in vacuo. The mixture was separated by flash chromatography on silica gel using EtOAc/Hexanes with increasing polarity (40:60 to 60:40) as the eluent. The least polar compound 129 was isolated as a white solid (31 mg, 31% yield) and the most polar compound was further purified by crystallization from a mixture of ethyl acetate and hexanes affording compound 128 as light beige crystals (18 mg, 18% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]([OH:7])=[O:6].[CH3:19]OC(OC)OC.O>C(O)=O>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[C:10]3[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[N:1]=[CH:19]2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(C(=O)O)ccc1Nc1cccc(F)c1
Reactant: COC(OC)OC
Solvent: O=CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)ncn2-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-amino-4-(3-fluorophenylamino)benzoic acid (4.96 g, 20.1 mmol) in formic acid (40 mL) was charged with trimethylorthoformate (2.4 mL, 22.0 mmol) and heated at reflux for 3 h after which time the mixture was allowed to cool to rt and stir for 12 h. The reaction mixture was then poured into 150 mL of H2O and stirred for 20 min yielding a precipitate which was isolated by filtration to give 1-(3-fluorophenyl)-1H-benzimidazole-5-carboxylic acid as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.75-7.66 (m, 3H), 7.59 (d, J=8.0 Hz, 2H), 7.38 (t, J=8.8 Hz, 1H); MS (ES+): m/z 257 [MH+].
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH:13]([CH3:15])[CH3:14].[Cl:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28](Cl)=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2>>[Cl:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28]([NH:1][N:2]4[C:11](=[O:12])[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=[C:3]4[CH:13]([CH3:15])[CH3:14])=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2
Reactant: O=C(Cl)CC12CC3CC(CC(Cl)(C3)C1)C2
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC12CC3CC(CC(Cl)(C3)C1)C2

Procedure:
3-Amino-2-isopropyl-4(3H)-quinazolinone and the product of Example 21A were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21-1.26 (m, 6H), 1.51-1.74 (m, 6H), 1.99-2.19 (m, 8H), 2.25 (s, 2H), 3.08-3.17 (m, 1H), 7.51-7.56 (m, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.82-7.88 (m, 1H), 8.13 (dd, J=7.9, 1.6 Hz, 1H), 10.89 (s, 1H) ppm; MS (DCI/NH3) m/z 414 (M+H)+; Elemental Analysis: Calculated for C23H28ClN3O2: C, 66.74; H, 6.82; N, 10.15. Found: C, 66.65; H, 6.82; N, 10.03.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[CH:11])[CH2:5][CH2:4]1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12)[NH2:16]>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[C:11][C:28]2[S:29][C:22]3[C:23](=[N:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=3[F:12])[CH:27]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCN(CC)CC1
Product: CCN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 50 °C
Yield: 45 %

Procedure:
Prepared from 1-ethyl-4-(prop -2-ynyl)piperazine (59 mg, 0.39 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 100 mg, 0.26 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (48 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6 Hz, 1H), 7.58 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.53 (m, 2H), 6.47 (m, 1H), 3.86 (br s, 2H), 3.60 (s, 2H), 2.45-2.74 (m, 8H), 2.46 (q, J=7 Hz, 2H), 1.11 (t, J=7 Hz, 3H).