Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)#[N:2].ClC1C=C(NC(=NC#N)OC2C=CC=CC=2)C=CC=1.[CH3:39][C:40]1[C:48]2[C:47]([N:49]3[CH2:54][CH2:53][NH:52][C@@H:51]([CH3:55])[CH2:50]3)=[N:46][CH:45]=[N:44][C:43]=2[NH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([N:3]=[C:4]([N:52]1[CH2:53][CH2:54][N:49]([C:47]2[C:48]3[C:40]([CH3:39])=[CH:41][NH:42][C:43]=3[N:44]=[CH:45][N:46]=2)[CH2:50][C@@H:51]1[CH3:55])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)#[N:2]
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: N#CN=C(Nc1cccc(F)c1)Oc1ccccc1
Agent: N#CN=C(Nc1cccc(Cl)c1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(F)c4)[C@@H](C)C3)c12
Temperature: 85 °C
Yield: 27 %

Procedure:
Phenyl N′-cyano-N-(3-fluorophenyl)carbamimidate, prepared analogously to phenyl N-3-chlorophenyl-N′-cyanocarbamimidate from Example 6, step A, (0.55 g, 2.2 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from example 1, step B, (0.50 g, 2.2 mmol), and N,N-diisopropylethylamine (1 ml) were added to acetonitrile (10 ml). The mixture was heated at 85° C. in a sealed pressure tube for 4 hours. The solvent was evaporated, and the residue was purified prep HPLC (Sunfire C18 30×250 mm column. 10-100% MeCN:H2O (10 mM NH4OAc), 18 min., 45 ml/min) to give (S)—N′-cyano-N-(3-fluorophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (0.23 g, 0.58 mmol, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[N:16][N:17]=2)[CH:14]=1.B.C1COCC1>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH2:18][NH2:19])=[CH:11][C:12]2[N:13]([CH:15]=[N:16][N:17]=2)[CH:14]=1
Reactant: N#Cc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 2.4 %

Procedure:
In a sealed flask, a solution of 6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (50 mg, 0.164 mmol) in THF (0.5 mL) was cooled to 0° C. (ice bath) then treated with BH3.THF complex (1.0 M solution in THF, 0.82 mL, 0.82 mmol). The reaction mixture was heated at 40° C. for 1 h, cooled to RT, and diluted in MeOH (large excess). The mixture was concentrated under vacuum, and the remaining residue was suspended in 2.0 M HCl, and shaken for 15 min. After evaporation to dryness, the remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 1.9 mg, 0.004 mmol, 2%) as a white solid. MS: 293 [M+1]+; HPLC: AtRet=0.95.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:15][CH2:16][C:17]1([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:21][CH2:20][NH:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:15][CH2:16][C:17]1([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH2:21][CH2:20][N:19]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:3][CH2:4]2)[CH2:18]1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCN(C2CCC(O)(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
100 mg (0.53 mmol) of 4-hydroxy-4-phenylcyclohexanone and 184 mg (0.53 mmol) of N-(2-{[3-(fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide were dissolved in 10 mL of methylene chloride. To the solution was added 221 mg (1.06 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 h. Direct chromatography on silica gel gave the final desired product 41 mg (top spot on TLC and first peak on HPLC, yield: 16.7%, MS: 522 (M+1)+) and the other isomer 51 mg (second peak on HPLC, yield: 20%, MS: 522 (M+1)+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:23]([N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:15])[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25]
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1ccccc1Cl
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2ccccc2Cl)c1
Yield: 39.1 %

Procedure:
The procedure is as in Example 1, but using 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.2 g of tert-butyl (RS)-2-anilino-2-(2-chlorophenyl)acetate and 0.72 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: dichloromethane/methanol (99/1 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from a mixture of acetonitrile and isopropyl ether (10/90 by volume). 2 g of tert-butyl (RS)-2-(2-chlorophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 181° C. are then obtained.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[C:30]([CH2:35]Br)=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(#N)C.C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:35][C:30]5[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: BrCc1ccccc1CBr
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α'-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH:9]([CH:11]=O)=O.CCCC(C)C.CCOC(C)=O.[K+].[Br-]>C(O)C>[N:8]1[CH:11]=[CH:9][N:1]=[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=12
Reactant: Nc1ccncc1N
Reactant: O=CC=O
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: c1cc2nccnc2cn1
Temperature: 70 °C

Procedure:
2.00 g (18.33 mmol) of 3,4-diaminopyridine were added to a solution of 2.82 ml of glyoxal (40 wt. % in water, ρ=1.265 g/ml, 62.48 mmol) in 30 ml of ethanol. The reaction mixture was maintained at an oil bath temperature of 70° C. for 5 hours and after cooling to room temperature the solvent was distilled off on a rotary evaporator. The crude product was purified by flash chromatography (EtOAc/isohexane, 9:1). This gave 2.35 g (17.96 mmol, 98%) of a white powder. Rf=0.27 (isohexane/EtOAc, 1:9). 1H NMR (200 MHz, CDCl3): δ=7.94 (dd, 3J=5.8 Hz, 4J=0.6 Hz, 1H, H-7), 8.83 (d, 3J=5.8 Hz, 1H, H-8), 8.96 (d, 3J=1.6 Hz, 1H, H-3), 9.02 (d, 3J=1.6 Hz, 1H, H-2), 9.56 (d, 4J=0.6 Hz, 1H, H-5) ppm. 13C NMR (100 MHz, CDCl3): δ=121.6 (CH, C-7), 138.0 (Cq), 145.3 (Cq), 147.3 (C—H, C-8), 146.5 (C—H, C-3), 149.2 (CH, C-2), 154.8 (C—H, C-5) ppm. GC-MS (EI): RT 5.45 min, m/e (%): 132 (8), 131 (M+, 100), 104 (25), 77 (13), 50 (10) IR (KBr): ν=3435 (vs), 3092 (w), 3023 (m), 1969 (w), 1758 (w), 1631 (w), 1598 (vs), 1562 (m), 1536 (w), 1488 (s), 1436 (vs), 1416 (m), 1381 (m), 1351 (w), 1290 (w), 1279 (m), 1212 (m), 1201 (m), 1148 (w), 1033 (s), 1014 (s), 972 (w), 959 (vs), 931 (m), 881 (vs), 838 (m), 824 (s), 773 (w), 651 (s), 623 (m), 546 (w), 524 (w), 457 (s) cm1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[I:13]Cl>C(O)(=O)C>[Br:1][C:2]1[C:3]([C:9]([F:10])([F:11])[F:12])=[CH:4][C:5]([NH2:8])=[C:6]([I:13])[CH:7]=1
Reactant: ClI
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)c(Br)cc1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
4-Bromo-3-trifluoromethyl-phenylamine (1.00 g, 4.17 mmol) was dissolved in acetic acid (5 ml). Iodine monochloride (1 M solution in dichloromethane, 5 ml) was added and the mixture was stirred at 60° C. overnight. The reaction solution was poured into a mixture of ice and a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution, an aqueous sodium thiosulfate solution, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 4-bromo-2-iodo-5-trifluoromethyl-phenylamine (889 mg, 58%).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH2:32]O)[C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:22]=3[Cl:34])=[C:17]([F:35])[CH:16]=2)[C:12]([CH3:36])=[N:11][C:10]=1[CH3:37])(=[O:8])[NH2:7].C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[C:6]([C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[CH2:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:22]=3[Cl:34])=[C:17]([F:35])[CH:16]=2)[C:12]([CH3:36])=[N:11][C:10]=1[CH3:37])(=[O:8])[NH2:7]
Reactant: COC(=O)C(CO)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C(=O)OC)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
Methanesulfonyl chloride (0.145 L, 1865 mmol) was added over 5 minutes to a stirred solution of methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)-3-hydroxypropanoate (Intermediate 31-8; 488 g, 1065 mmol) and triethylamine (0.520 L, 3730 mmol) in tetrahydrofuran (5.0 L) at 10° C. The reaction was heated to 50° C. and left stirring for 2 hours. The reaction was then cooled to 20° C. The mixture was diluted with ethyl acetate (10.0 L), then water (3.0 L) was added. Saturated aqueous ammonium chloride solution (4.1 L) was added. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2.5 L). The organics were combined, washed with 50% brine/water (5.0 L), dried (magnesium sulphate), filtered and the solvent removed in vacuo. The crude product was dissolved in dichloromethane and then chromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column), eluting with a solvent gradient of 0-70% ethylacetate/isohexane. Pure fractions were evaporated to dryness to afford methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoate (188 g, 40%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:21]([CH3:23])[CH3:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8][C:7]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+].CO.O>>[CH3:1][O:2][C:3]1[C:4]([N:21]([CH3:23])[CH3:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: COc1nc2c(cc1N(C)C)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc2c(cc1N(C)C)C(C)CNCC2
Yield: 68.2 %

Procedure:
NaBH3CN (63.0 mg, 990 μmol) was added portionwise at room temperature to a solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (100 mg, 330 μmol) and HCHO (37% in H2O, 2.31 mmol) in MeCN (1 ml). The mixture was stirred at room temperature for 15 min before slow addition of HOAc (0.2 ml). The reaction was stirred at room temperature for an additional 3 h and was basified with aq. K2CO3 and extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 94.0 mg (86%) of 2-methoxy-N,N,5-trimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. MS (ESI) m/z 332. 2-Methoxy-N,N,5-trimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (35.0 mg, 106 μmol) was treated under basic condition (K2CO3/MeOH/H2O), as described above, to provide 17 mg (68%) of 2-methoxy-N,N,5-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. MS (ESI) m/z 236.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2c(-c3ccncc3)[nH]c(=O)n(C)c2=O)c1
Product: Cc1cccc(-c2c(-c3ccncc3)nc(Cl)n(C)c2=O)c1

Procedure:
A mixture of 3-methyl-5-(3-methylphenyl)-6-(4-pyridyl)-2,4(1 H,3 H)-pyrimidindione (12.5 g, 0.043 mol) and phosphorus oxychloride (65 ml) was refluxed for 16 h. The excess of phosphorus oxychloride was evaporated followed by co-distillation with toluene. The remainder was carefully partitioned between dichloromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with water, dried and evaporated to leave the title compound. MS (m/z): 312 (M)+ ; C17H14ClN3O requir. 311.8.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1>>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:15][C:16]=2[NH2:21])=[O:9])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: NCc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cc1
Yield: 31.5 %

Procedure:
The title compound (195 mg, 63% yield) was prepared as a grey solid from 4-cyano-benzoic acid (294 mg, 2 mmol) and 4-trifluoromethyl-o-phenylenediamine (422 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 310 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[OH:29].[H-].[Na+]>CC(N(C)C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:30][C:31]([OH:33])=[O:32])=[CH:24][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(Oc2ccc(CC(=O)O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 142.8 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.6 g, 5.32 mmol), (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.8 g, 10.64 mmol), and sodium hydride (638 mg, 26.61 mmol) in dimethylacetamide (18 mL) was heated under microwave irradiation for 1 hr at 150° C. The reaction was quenched with water and the product extracted in ethyl acetate. The organic layer was concentrated in vacuo and purified by flash chromatography to provide compound C149 as a white solid (3.4 g, 48%). 1H NMR (DMSO-d6, 400 MHz) δ 1.12 (d, 6H), 1.53-1.63 (m, 2H), 1.82-1.92 (m, 2H), 2.07 (s, 3H), 3.22-3.31 (m, 2H), 3.37-3.52 (m, 2H), 3.52-3.61 (m, 2H), 4.71 (h, 1H), 5.19-5.28 (h, 1H), 7.06 (d, 1H), 7.16-7.23 (m, 2H), 8.17 (s, 1H). Exact mass calculated for C22H26FN3O6 447.46, found 448.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH:42]1(N)[CH2:46]C[CH2:44][CH2:43]1.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:37]1([CH2:36][NH:35][CH2:34][CH2:33][N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]3)[CH:29]=[N:30]2)[CH2:44][CH2:43][CH2:42][CH2:46]1
Reactant: NC1CCCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Solvent: NCCO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCC5CCCC5)c4)cc23)CC1
Yield: 40 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclopentanamine (37 mg, 0.43 mmol) for the 2-aminoethanol to afford 11 mg of the title compound (40%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:33])[C@@H:20]([NH:25]C(OC(C)(C)C)=O)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:34])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:33])[C@@H:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:34])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.2 %

Procedure:
To a solution of 4-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan-1-carboxylic acid benzyl ester of Example 2f (4.0 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 2 hours whereupon it was concentrated to provide the title compound (3.8 g): MS(EI) 378 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][NH:6][C:7]([NH:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][N:6]([CH2:30][CH3:31])[C:7]([NH:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=[O:8]
Reactant: CCI
Reactant: CC(C)(NC(=O)NOc1cc(Cl)cc(Br)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(Oc1cc(Cl)cc(Br)c1)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2.89 g of 1-(3-bromo-5-chlorophenoxy)-3-(2-phenylpropan-2-yl)urea was dissolved in 30 ml of N,N-dimethyl formamide. The resulting solution was added to a mixture of 5.18 g of potassium carbonate and 1.17 g of iodoethane, followd by stirring for one night at room temperature. Ethyl actate was then added to the susulting solution. The resulting mixture was washed with ammonium chloride, and the organic layer was dried with magnesium sulfate. After filtration, the solvent was distilled off. The resulting residues was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=5:1) to obtain the target compound of 1-(3-bromo-5-chlorophenoxy)-1-ethyl-3-(2-phenylpropan-2-yl)urea (2.86 g, yield: 92%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 4-tert-butoxycarbonylamino-1-N-(3,3-diphenylpropyl)piperidine (Method J) (10 g, 25 mmol) in DCM (100 ml) was added trifluoroacetic acid (20 ml) dropwise. After 3 h, toluene was added and the reaction mixture was concentrated to give the di-trifluoroacetic acid salt of the title compound as an oil (9.7 g, 19 mmol); MS: 295.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.F[C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[CH:13]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1cccc(F)c1F
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: O=C1CC(c2cccc(F)c2)Oc2ccc(Br)cc21
Yield: 15 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (22.6 g, 0.11 mol), 2,3-difluoro-benzaldehyde (15 g, 0.11 mol) and borax (40.2 g, 0.11 mol) in ethanol (140 mL) and H2O (234 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (5.3 g, 15%). 1H-NMR (CDCl3): 2.95 (d, 1H), 3.05 (t, 3H), 5.75 (d, 1H), 6.97 (d, 1H), 7.20 (m, 2H), 7.35 (m, 1H), 7.60 (d, 1H), 8.05 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([C:13](Cl)([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:32][CH:31]=2)([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: COc1ccc(C(Cl)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(Br)cn2)cc1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a suspension of 4-bromopyrazole (1.5 g, 10.2 mmol) and 4,4′,4″-trimethoxytrityl chloride (4.5 g, 12.2 mmol) in anhydrous DMF (20 mL) under argon was added triethylamine (3 mL, 21.5 mmol) and the mixture was cooled over an ice bath. After stirring for 10 min, the ice bath was removed and the reaction stirred for 2.5 hrs. The mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with H2O three times then saturated aqueous NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo. The crude oil was recrystallized from isopropanol to give 4-bromo-1-(tris(4-methoxyphenyl)methyl)-1H-pyrazole as off-white crystals (two batches; 2.55 g, 52% yield).