Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([O:49][CH2:50][C:51]([F:54])([F:53])[F:52])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:55]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([O:49][CH2:50][C:51]([F:54])([F:52])[F:53])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:55]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.7 g) was dissolved in ethanol (150 ml), and to the solution, sodium borohydride (0.24 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 21) (1 g) as yellow amorphous.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7](SC)[N:6]2[CH:11]=[CH:12][N:13]=[C:5]2[CH:4]=1.[OH-:14].[K+].CS.Cl>CO.O>[Cl:2][C:3]1[NH:8][C:7](=[O:14])[N:6]2[CH:11]=[CH:12][N:13]=[C:5]2[CH:4]=1
Reactant: CSc1nc(Cl)cc2nccn12
Reactant: [OH-]
Agent: CS
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1[nH]c(Cl)cc2nccn12
Yield: 87.5 %

Procedure:
7-Chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (10.5 g, 44.5 mmol) was partially dissolved in MeOH (40 mL) and then a solution of potassium hydroxide (11.2 g, 200 mmol) in water (100 mL) was slowly added and the reaction was heated to reflux. The reaction generates methane thiol, so caution was taken to contain this noxious gas in the hood. After 2 hours the reaction was cooled and then neutralized with a solution of 1N HCl to reach a pH of between 6 and 7. The reaction was filtered and the solid was washed with MeOH. The solids were dried on the filter cake and then dried on a high vacuum pump to provide 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (6.6 g, 87% yield) as a white solid. MS (apci) m/z=170.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Li+]>O1CCCC1.O.Cl>[Cl:1][C:2]1[C:3]([O:13][CH:14]2[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of methyl 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate (0.314 g, 0.973 mmol) in tetrahydrofuran (15 mL) and water (10 mL) was added lithium hydroxide (0.148 g, 6.18 mmol). The mixture was heated to reflux for 1.5 hours, cooled to ambient temperature. The reaction was diluted with 1 M hydrochloric acid (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography, with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50% to afford the title compound as a colorless solid (0.25 g, 83%): 1H NMR (300 MHz, CDCl3) 8.05 (d, J=7.6 Hz, 1H), 6.70 (d, J=12.1 Hz, 1H), 4.63 (br s, 1H), 2.52-1.90 (m, 8H); 19F NMR (282 MHz, CDCl3) δ −92.3 (d, J=238 Hz, 1F), −102.6 (d, J=238 Hz, 1F), −105.3 (s, 1F); MS (ES−) m/z 307.2, 309.2 (M−1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([NH2:36])[N:27]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][CH:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:38]([O:41][C:42](=[O:43])[NH:44][CH:45]([CH3:49])[C:46]([NH:36][C:28]1[N:27]=[C:26]([Br:25])[C:35]2[C:30]([CH:29]=1)=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([CH3:40])([CH3:37])[CH3:39]
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
HATU (7.5 g, 19.7 mmol) is added to a mixture of 1-bromoisoquinolin-3-amine (2.0 g, 9.0 mmol), 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.7 g, 9.0 mmol) and DIPEA (3.4 ml, 200 mmol) in DMA (10 ml). After stirring for 3 days at RT the mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 3.3 g (94%). HPLC-MS: M−H=392/394; tR=1.97 min (*Method—1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.CCCCC>[Cl:1][C:2]1[C:11]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1c(Cl)ccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCCCC
Product: O=S(=O)(Nc1c(Cl)ccc2cccnc12)c1ccccc1
Yield: 61.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-chloroquinolin-8-amine (Intermediate 52) (100 mg, 0.56 mmol), benzenesulfonyl chloride (110 mg, 0.67 mmol) and DMAP (cat.) gave the title compound (110 mg, 56%) after trituration from n-pentane.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:12]>>[OH:12][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=S(=O)(O)O
Product: Oc1ccc2cn[nH]c2c1
Reaction time: 1 h
Yield: 51 %

Procedure:
6-aminoindazole (2.66 g, 20 mmol) is added to 20% of dilute sulfuric acid and the reaction is performed under microwave radiation at 170° C. for 1 hour using microwave powder of 600 watt, and then terminated. The reaction solution is cooled, adjusted to pH=7 with 5% NaOH and stirred for 10 minutes to precipitated a deposit, which is recrystallized in water to obtain 1.5 g of 6-hydroxyindazole, with a yield of 51%.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][NH:30][CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][N:30]([CH3:31])[CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: CNC
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A mixture of 400 (360 mg, 0.91 mmol) and dimethylamine (2M THF solution, 550 μL, 1.09 mmol) in DCM (10 mL) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (270 mg, 1.27 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 10-30% MeOH in DCM as an eluent, to provide title compound 402 (321 mg, 83% yield). MS (m/z): (M+1) 425.1 (100%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]([O:26]C)=[O:25])=[O:21])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:33])[C@H:13]([CH2:14][S:15]2(=[O:29])=[O:28])[C@:12]2([CH3:30])[C@H:7]([C:8]([CH3:32])([CH3:31])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1.O[Li].O>CO.O>[OH:1][C:2]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:33])[C@H:13]([CH2:14][S:15]2(=[O:29])=[O:28])[C@:12]2([CH3:30])[C@H:7]([C:8]([CH3:32])([CH3:31])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1
Reactant: COC(=O)CNC(=O)c1cc(O)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(C(=O)NCC(=O)O)cc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
A mixture of methyl 2-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]-formamido}acetate (92) (0.07 g, 0.2 mmol) and LiOH.H2O (0.07 g, 2 mmol) in MeOH (10 mL) and water (2.0 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, the aqueous residue was acidified with 1 M HCl and the resulting solid was collected by filtration to give 2-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]formamido}acetic acid (93) (0.057 g, 84%) as a pale brown solid. 1H NMR (CD3OD): δ 7.79 (d, 1H), 7.43 (d, 1H), 4.07 (s, 2H), 3.60 (d, 1H), 3.38 (m, 2H), 2.26 (d, 1H), 1.86-1.16 (m, 12H), 1.10-1.00 (m, 5H), 0.90 (s, 3H), 0.88 (s, 3H). MS m/z 462 (C24H33NO6S−H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH2:26]([N:22]1[CH2:23][C:24](=[O:25])[N:9]2[C@H:10]([CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=3[C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][CH:4]=2)[C:21]1=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(NS(C)(=O)=O)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O

Procedure:
To a solution of Example 98 (0.2 g) in THF (5 mL) was added triethylamine (228 μL) and methanesulfonyl chloride (126 μL) and the solution was heated at reflux for 6 hours. After evaporation of THF, the residue was taken up in CH2Cl2, washed with water, and dried over Na2SO4. After evaporation of CH2Cl21 the residue was purified by radial chromatography eluting with CH2Cl2 /MeOH (95/5) to give the title compound as a brown powder (30 mg) m.p.: 188° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:6]([O:8]C)=[O:7])(=[O:3])C.Cl.[OH-].[Na+].[O-]C#[N:23].[K+]>>[O:17]=[C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[CH2:10][CH:5]([NH:4][C:1]([NH2:23])=[O:3])[C:6]([OH:8])=[O:7]
Reactant: N#C[O-]
Reactant: COC(=O)C(CC1CCCCC1=O)NC(C)=O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: NC(=O)NC(CC1CCCCC1=O)C(=O)O
Temperature: 92.5 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
Methyl 2-acetamido-3-(2-oxocyclohexyl)propanoate (15.0 g, 62.2 mmol, prepared as described in EP 84164) was dissolved in 30 mL 6N HCl aq. (180 mmol) and heated at 90-95° C. for 4 h. The resulting reaction mixture was cooled in an ice-bath and neutralized to pH 7.0 with 23 mL 10N NaOH aq. (230 mmol), maintaining the temperature at 15-25° C. Then, potassium cyanate (4.8 g, 69 mmol) was added and the mixture was heated to 60° C. After 3 h, the solution was cooled to 50° C. Decolorizing carbon (1.0 g, Norit SX) was added, stirred for 0.5 h and the carbon was filtered off under suction. The remaining solution (pH 8.9) was cooled in an ice-bath and acidified with 6N HCl aq., maintaining the temperature below 10° C. At pH 4.5, the solution was seeded with 0.1 g product. At pH 1.8, the slurry was stirred for 0.5 h and then the product was collected on a filter under suction. The off-white crystals were dried under vacuum. Weight 4.20 g, approximately 30% yield. 1H NMR: (DMSO-d6, 300 MHz): δ 12.45 (br s, 1H), 6.22 (dd, 1H), 5.60 (br s, 2H), 4.19-3.95 (m, 1H), 2.45-1.15 (m, 11H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.ClC1C=CC(C(=O)C)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([O:37][CH2:38][CH2:39]Br)[CH:34]=[CH:35][CH:36]=1>C(N(CC)CC)C.O.C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:39][CH2:38][O:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=2)[CH2:5][CH2:4]1
Reactant: Clc1cccc(OCCBr)c1
Reactant: NCC1CCNCC1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NCC1CCN(CCOc2cccc(Cl)c2)CC1

Procedure:
In a similar manner to Example 7, a mixture of 4-aminomethylpiperidine (2.9 g), 4'-chloroacetophenone (3.94 g), toluene (100 ml) and a catalytic amount of p-toluenesulphonic acid was boiled under reflux for five hours with removal of the water formed using a Dean and Stark apparatus. The mixture was cooled and treated with 2-bromoethyl 3-chlorophenyl ether (6.0 g) followed by triethylamine (3.54 ml). The mixture was boiled under reflux for 6 hours and then evaporated to dryness. 6M Hydrochloric acid (50 ml) was added and the mixture heated on a steam bath for 16 hours to give 4-aminomethyl-1-[2-(3-chlorophenoxy)ethyl]piperidine, as an oil. The oil, obtained on work up, was treated with 98% formic acid (5.0 ml) and formaldehyde (5.0 ml, 38% aqueous solution). The mixture was heated on a steam bath for 4 hours. After extractive work up as described in Example 7, the oil obtained was distilled at 120° C. at 0.13 mbar. The distillate was treated with ethereal hydrogen chloride to give 1-[2-(3-chlorophenoxy)ethyl]-4-(dimethylaminomethyl)piperidine dihydrochloride, m.p. 258°-260° C., after recrystallisation from absolute ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CCN=C=NCCCN(C)C.Cl.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c3c(n(C)c12)C(=O)N(C)CC3
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3

Procedure:
A solution of 8-methoxy-2,9-dimethyl-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxylic acid (from step 5) (1 mmol), p-nitrophenol (1.5 mmol), EDCl (1.5 mmol) and DMAP (0.1 mmol) in dry THF was stirred at r.t. for 18 h. Minimum water was then added and the precipitated p-nitrophenylester was filtered and washed with water and dried (50-60%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:31]=[CH:30][C:20]([CH2:21][N:22]3[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]3)=[CH:19][C:18]=1[F:32])=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O.CC(O)=O>[F:32][C:18]1[CH:19]=[C:20]([CH2:21][N:22]2[CH2:23][CH:24]([C:26]([OH:28])=[O:27])[CH2:25]2)[CH:30]=[CH:31][C:17]=1[C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:16][CH:15]=2
Reactant: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 1-(4-(5-benzyl-1H-indol-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate (0.090 g, 0.21 mmol) in THF (1.0 mL) and water (1.0 mL) was added lithium hydroxide (0.025 g, 1.1 mmol). The solution was stirred at rt for 1 h, or until starting material was no longer observed by LCMS. The solvent was removed under reduced pressure, and 0.5M phosphate buffer (3.0 mL, pH 6.0) was added (pH was ca. 9-10). The mixture was acidified with 1N HCl to pH 6.0 and sonicated for 5 min. The aqueous solution was extracted with EtOAc (3×15 mL), and the separated organic extracts were dried over MgSO4, filtered and concentrated to afford a brown oil. The oil was dissolved in AcOH (3.0 mL), and the excess AcOH was removed under reduced pressure. Ether (15 mL) was added, and the resulting precipitate was collected by filtration. The brown solids were washed with water (10 mL) and chloroform (15 mL) to afford title compound as a yellow solid [hS1P1 EC50=1336 nM]. MS (ESI) m/z: Calculated: 414.1; Observed: 415.1 (M++1).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].C(O)C.[CH2:40]([NH:42][CH2:43]C)C>CN(C=O)C>[C:1]([N:3]=[C:4]([N:42]([CH3:43])[CH3:40])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)C(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
100 mg of the product of Example 50 were treated with 10 ml of ethanol, 10 ml of DMF and 20 ml of 40% aqueous diethylamine for 16 hours. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 53 mg of 3-[1-[3-(2-cyano-3,3-dimethylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p 150°-153° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[CH3:13][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([O:8][CH3:13])=[O:7])#[N:2]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.7 %

Procedure:
To a solution of 3-cyano-5-fluorobenzoic acid (1.0 g, 6.1 mmol) in dichloromethane (5 ml) and methanol (0.5 ml), at 0° C., was added dropwise (trimethylsilyl)diazomethane (2M in hexanes, 3.6 ml, 7.3 mmol). The reaction mixture was stirred at room temperature, under nitrogen, for 18 h and then concentrated in vacuo to give the title compound (1.1 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[CH:20]=1)=[N+]=[N-]>C(O)C.[Pd]>[C:14]1([C:12]2[NH:11][C:10]3[CH:20]=[C:6]([CH2:5][CH2:4][NH2:1])[CH:7]=[CH:8][C:9]=3[N:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=NCCc1ccc2nc(-c3ccccc3)[nH]c2c1
Agent: [Pd]
Solvent: CCO
Product: NCCc1ccc2nc(-c3ccccc3)[nH]c2c1
Reaction time: 2 h

Procedure:
Azide 192 was dissolved in ethanol and 10% Pd/C (50 mg) was added. H2 was applied at 40 psi with vigorous shaking. After 2 h, TLC analysis indicated complete consumption of starting material. The heterogeneous reaction mixture was filtered through Celite, and the filtrated was concentrated under reduced pressure to give 193.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]([CH3:19])=[CH:18][C:9]1=2.[CH:39]([C:41]1[S:45][C:44]([C:46]([OH:48])=[O:47])=[CH:43][CH:42]=1)=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:39][C:41]2[S:45][C:44]([C:46]([OH:48])=[O:47])=[CH:43][CH:42]=2)[C:10]2[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(C(=O)O)s1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1

Procedure:
To a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (6.10 mmol) in dichloroethane (5 mL), add 5-Formyl-thiophene-2-carboxylic acid (0.4 mmol) followed by acetic acid (cat.). Add NaB(OAc)3H (0.5 mmol) and stir the mixture at room temperature for 14 h. Dilute the reaction with dichloromethane (10 mL) and quench with water (5 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over Na2SO4, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with MeOH/DCM (1-5%) to provide the title compound as a colorless foam. MS (ES+): 693 (M+H).
Reaction SMILES: [CH:1]([CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:4](OC)=O)=[O:2].Cl.[CH:19]([NH2:21])=[NH:20].C(N(C(C)C)C(C)C)C>C(O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:3]2[C:1](=[O:2])[NH:21][CH:19]=[N:20][CH:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COC(=O)C(C=O)c1ccc(OC)c(OC)c1
Reactant: N=CN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc[nH]c2=O)cc1OC
Yield: 23 %

Procedure:
Methyl 2-formyl-2-(3,4-dimethoxyphenyl)acetate (7.2 g) (30 mmol), 4.8 g (60 mmol) of formamidine hydrochloride and 7.74 g (60 mmol) of N-ethyldiisopropylamine (Hunig base) are stirred in 60 ml of ethanol for 55 hours at 50° C. and subsequently concentrated in a vacuum. The residue is washed several times with diethyl ether and then crystallized using ethanol/diethyl ether. The yellowish product is filtered off under suction, washed with ethanol/diethyl ether and dried in a high vacuum at room temperature. There are obtained 1.6 g of 5-(3,4-dimethoxyphenyl)-4(3H)-pyrimidinone of m.p. 205°-206° C.