Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[CH:11]#[N:12].OP(O)(O)=O>[C-]#N.C([N+](CC)(CC)CC)C>[O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([C:4]1([CH3:10])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1)#[N:12]
Reactant: C#N
Agent: CC[N+](CC)(CC)CC
Agent: O=P(O)(O)O
Agent: [C-]#N
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CC(=O)CC(C)(C#N)C1

Procedure:
To 415 g (3 mol) of isophorone containing 12 g (0.077 mol) of tetraethylammonium cyanide there are added dropwise, over a period of 1 hour, 81 g (3 mol) of hydrogen cyanide at a reaction temperature of 108° C. Following a post-reacting period of 3 min the HCN concentration is 0.16%. The effluent is neutralized with 9 g of H3PO4 and distilled. There are obtained 15 g of isophorone and 443.6 g of 3-cyano-3,5,5-trimethylcyclohexanone. This is equivalent to a yield of 89.6% based on HCN used and 93% based on converted isophorone. The distillation residues weigh 28.2 g, which is equivalent to 5.5% based on crude product used.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[CH:18]=2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5](=[O:27])[C:4]([OH:28])=[O:3])=[CH:7][CH:8]=2)=[CH:18][C:19]=1[OH:26])(=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCOc2ccc(C(C)=O)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(OCCCOc2ccc(C(=O)C(=O)O)cc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
As in example 10, 4-[3-(4-acetyl-3-hydroxyphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.7 g) in methanol (70 mL) was treated with a solution of sodium carbonate (0.42 g) in water and brought just to reflux temperature, then was allowed to cool to room temperature. After 1 hour, most of the methanol was removed in vacuo, then the mixture was diluted with water, acidified with 3N hydrochloric acid and extracted twice with dichloromethane-tetrahydrofuran (1:1). Evaporation of the dried (MgSO4) extracts and crystallization of the solid residue from dichlorornethane-hexane afforded 0.58 g of 4-[3-(4-acetyl-3-hydroxyphenoxy)propoxy]-alpha-oxobenzeneacetic acid, mp 133°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH3:15]>CN(C)C=O>[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:4][C:3]1[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][C:2]=1[F:1])[CH3:15]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CN(C)CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCCOCc1cc(Br)ccc1F

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (967 mg, 3.61 mmol) was dissolved in N,N-dimethylformamide (3.5 ml). To this solution sodium hydride (60%, 245 mg, 6.14 mmol) was added and the resulting mixture was stirred for ten minutes. To the reaction mixture 4-(N,N-dimethylamino)butanol (633 mg, 5.41 mmol) was added and the rsulting mixture was stirred for six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: [S:1]=[C:2](C(S)C(OCC)=O)[CH3:3].[NH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH2:12].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2].C(OC(C)C)(C)C>ClCCl>[S:1]=[C:2]([NH:12][NH:11][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:3]
Reactant: CCOC(=O)C(S)C(C)=S
Reactant: CCOC(=O)NN
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CCOC(=O)NNC(C)=S
Yield: 79 %

Procedure:
A mixture of 110 g of 2-(1-thioxoethyl)thioglycolic acid, ethyl ester, 65.2 g of ethyl hydrazinocarboxylate and 500 ml of dichloromethane was heated at reflux for 3 hours, then concentrated in vacuo. The oily residue was concentrated further under high vacuum, giving a yellow oil. This oil was dissolved in 500 ml of dichloromethane and passed through a bed of hydrous magnesium silicate, washing with additional dichloromethane. The resulting light yellow oil was crystallized from diisopropyl ether giving a 79% yield of the desired compound as ivory crystals, mp 54.0°-57.5° C. Proton nuclear magnetic resonance (δ [ppm], CDCl3) 90 MHz: 1.30 (t, 3 H, J=7.4 Hz, CH3CH2); 2.55 (s, 3H, CH3CS); 4.25 (q, 2H, CH2CH3); 8.75 (bs, 1H, NH); 10.35 (bs, NH).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>CO>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCC(=O)CC1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CC1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a solution of potassium hydroxide (22 g, 392 mmol) in methanol (160 mL) was added 5-benzyloxyindole (24.7 g, 111 mmol) followed by 1-methyl-4-piperidone (17.7 mL, 144 mmol) and methanol (80 mL). The reaction mixture was stirred at reflux for 18 h, cooled to ambient temperature and filtered. The precipitate was washed with methanol and dried under vacuum to give 31.7 g (90%) of the title compound: mp=197-199° C. dec; MS(m/e): 318 (M+). Calculated for C21H22N2O: C, 79.21; H, 6.96; N, 8.80. Found: C, 79.24; H, 6.99; N, 8.85.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[C:16]([CH3:17])=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)[Cl:20]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[C:16]([CH3:17])=[C:15]([Cl:20])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)N1CC2c3scc(C)c3C(C)C2C1
Solvent: ClCCl
Product: CCOC(=O)N1CC2c3sc(Cl)c(C)c3C(C)C2C1
Reaction time: 1 h

Procedure:
The product from step j) (316 mg, 1.19 mmol) was dissolved in CHCl3 (6 ml) and a solution of SO2Cl2 (95.6 μl, 1.19 mmol) in CHCl3 (1.6 ml) was added dropwise over 10 minutes. and the contents were stirred for 1 hour. Next, the mixture was diluted with CH2Cl2 (50 ml), washed with H2O (2×50 ml), sat. NaHCO3 (50 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the crude product was purified by silica-gel chromatography (hexanes:EtOAc-1:3) to give the subtitle compound. MS calculated for C14H18ClNO2S+H 300, observed 300.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:21][C@H:20]1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:27][NH:28]2)=[CH:24][CH:23]=1.[CH3:43][C:44]([CH3:46])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CO.CCOCC>[CH:44]([N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([C:26]3[C:25]4[C:29](=[CH:30][C:22]([C@H:20]5[C@@:13]6([C:12]7[C:16](=[CH:17][CH:18]=[C:10]([O:9][CH3:8])[CH:11]=7)[NH:15][C:14]6=[O:19])[CH2:21]5)=[CH:23][CH:24]=4)[NH:28][N:27]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1)([CH3:46])[CH3:43]
Reactant: CC(C)=O
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c1)C(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCN(C(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Temperature: 40 °C
Yield: 45.5 %

Procedure:
A solution of (1R*,2S*)-5′-methoxy-2-(3-(4-(piperazin-1-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one 2,2,2-trifluoroacetate (30 mg, 0.052 mmol) in 1,2-dichloroethane (0.5 mL), MeOH (0.1 mL) was treated with acetone (80 uL, 1.04 mmol) and NaBH(OAc)3 (17 mg, 0.078 mmol) and the reaction was heated to 40° C. for 18 h. The solvent was removed and the residue purified by column chromatography (silica gel, CH2Cl2/MeOH/7N NH3 in MeOH, 96:3:1) which gave an impure solid that was sonicated in Et2O. The solvent was decanted off and the solid dried to give the title product as an off-white powder (12 mg, 46%); 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 10.44 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.06-6.99 (m, 3H), 6.74 (d, J=8.5 Hz, 1H), 6.57 (d, J=7.5 Hz, 1H), 5.69 (s, 1H), 3.29 (s, 3H), 3.25-3.15 (m, 4H), 2.67 (m, 2H), 2.65-2.55 (m, 4H), 2.35-2.32 (m, 1H), 2.22-1.98 (m, 1H), 1.01 (d, J=5.6 Hz, 6H); MS ESI [M+H]+ 508.3, calcd for [C31H33N5O2+H]+ 508.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[N:11]([CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=3)=[O:26])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)n[nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NCc3cccc(C(F)(F)F)c3)c2=O)cc1

Procedure:
1.00 g (3.17 mmol) of 5-(4-chlorophenyl)-4-(4-methoxyphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 55A, 0.80 g (3.17 mmol) of 2-chloro-N-[3-(trifluoromethyl)phenylmethyl]-acetamide and 0.88 g (6.33 mmol) of potassium carbonate are suspended in 20 ml of acetonitrile and heated under reflux for 8 hrs. The mixture is then concentrated in vacuo, and the residue taken up in water and extracted three times with ethyl acetate. The combined organic phases are concentrated and the residue purified by preparative HPLC [Method 12]. 1.07 g (64% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: NCC(=O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NCC(=O)c1ccccc1
Yield: 85 %

Procedure:
The title compound (0.63 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (0.50 g) and 2-amino-1-phenylethanone (0.35 g) according to the method of description 54.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[C:16]=2[F:24])=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[CH2:22]([O:21][C:17]1[C:16]([F:24])=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:26])=[O:2])[C:10](=[O:25])[CH:11]=1)[CH3:23]
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OC)C2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution containing (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (2.40 g, 0.007 mol) in tetrahydrofuran (40 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 30 mL, 0.015 mol). The mixture was stirred at room temperature for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (2.00 g, 87%) as a white solid after triturating with diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]([NH2:10])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Temperature: 55 °C

Procedure:
To a stirred solution of [2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethy]-carbamic acid tert-butyl ester (2.5 g, 6.2 mmol) in THF (10 mL) and methanol (10 mL) was added hydrazine hydrate (3.1 g, 62 mmol). The mixture was heated a 55° C. for 1 hour. Then it was concentrated to dryness, dissolved in H2O (5 mL) and extracted with ethyl acetate (50 mL). The organic mixture was concentrated and purified by column chromatography (methanol:dichloromethane, 1:100) to afford [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester. (Yield 1.325 g, 79%). LC-MS: [M+H]+ 271.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[NH:17][C:18]([NH2:20])=[O:19]>O1CCOCC1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]1[C:3](=[O:4])[CH:2]=[C:1]([OH:6])[NH:20][C:18]1=[O:19]
Reactant: NC(=O)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1COCCO1
Product: O=c1cc(O)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C
Yield: 76.3 %

Procedure:
1.7 g of malonic acid dichloride was added dropwise to a 50 ml 1,4-dioxane solution of 2.4 g of 2,4,6-trichlorophenylurea with stirring at 0° C. The solution was stirred at room temperature for 3 hours and then the solvent was distilled away under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (developing solvent: chloroform) to obtain 2.35 g of 3-(2,4,6-trichlorophenyl)-6-hydroxy-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:17]1[CH:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2)c1
Yield: 35.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), biphenyl-3-carbonyl chloride (0.0965 g; 0.445 mmol), and triethylamine (0.145 mL; 1.06 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.0565 g (36%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cc(F)ccc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6cc(F)ccc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B79) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C10) and HBTU (304 mg) in DCM/DMF (15 ml/2 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and twice by preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluation gradient: EtOAc/methanol/triethylamine, 91/5/4 (v/v/v)] as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:11](O)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](O)=[O:15].O1CCOCC1.C(OCC)C>O>[C:11]1(=[O:21])[N:1]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Nc1n[nH]c2ccccc12
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
5.0 g of the same 3-aminoindazole as Example 1 and 6.68 g of phthalic acid were added to 50 ml of dioxane, and the mixture was stirred for 5 hours at 120° C. The mixture was condensed under reduced pressure, 30 ml of diethyl ether was added and the mixture was stirred under cooling with ice and water for 30 minutes to separate crystals. The crystals were obtained by filtration and dried under reduced pressure to give 8.6 g of 3-phthalimidoindazole in a yield of 87%.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[OH-].[NH4+:32].O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)[CH2:7][C:8]([NH2:32])=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12
Reactant: CC(C)Oc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Reactant: [NH4+]
Agent: CN(C)c1ccncc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of 3-phthalimido-3-(3,4-diisopropoxyphenyl)propionic acid (1.0 g, 2.4 mmol), 1,1 carbonyldiimidazole (0.43 g, 2.6 mmol), and 4-dimethylaminopyridine (trace) in tetrahydrofuran (18 mL) was stirred for 1.5 hours at room temperature. To the solution was added ammonium hydroxide (0.24 mL, 3.7 mmol, 28-30%) and stirring was continued for 2 hours. The tetrahydrofuran was removed in vacuo leaving an oil. To the oil was added 2 mL of water and the mixture was stirred at room temperature overnight. The resulting slurry was filtered, the solid was washed with water, air dried, and dried in vacuo (60° C., <1 mm) to afford 0.87 g (88%) of 3-phthalimido-3-(3,4-diisopropoxyphenyl)propionamide as a white solid: mp 153°-154.5° C.; 1H NMR (DMSO-d6) δ 7.92-7.78 (m, 4H), 7.55 (s, 1H), 7.03(s, 1H), 6.93-6.77 (m, 3H), 5.71-5.56 (m, 1H), 4.51-4.33 (m, 2H), 3.25-3.06 (m, 2H), 1.31-1.08 (m, 12H); 13C NMR (DMSO-d6) δ 171.7, 168.3, 148.9, 133.9, 132.1, 131.9, 123.3, 120.9, 117.7, 72.2, 72.1, 51.5, 37.9, 22.2; Anal. Calcd. for C23H26N2O5. Theoretical: C, 67.30; H, 6.38; N, 6.82. Found: C, 67.01; H, 6.35; N, 6.69.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][NH:20]3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].CCN(CC)CC.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([BH3-])#N.[Na+]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][N:20]3[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:29][CH:30]=1)#[N:3]
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2Cc2ccccc2)cc1
Reaction time: 18 h

Procedure:
1,2,3,4-Tetrahydro-isoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide hydrochloride (0.15 g, 0.33 mmol) was dissolved in MeOH (7 mL). Et3N was added to this solution dropwise until the pH=5. To the solution was added benzaldehyde (0.069 mL, 0.65 mmol) and sodium cyanoborohydride (0.041 g, 0.65 mmol). After stirring for 18 hr. the mixture was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification on silica gel eluting with CH2Cl2 :
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:60]2[CH:59]=[CH:58][C:57]([O:56][CH3:55])=[CH:62][CH:61]=2)(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methoxybenzenesulfonyl chloride as starting materials in 41% yield. LCMS for C31H33ClN7O4S (M+H)+: m/z=634.2.