Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2.[C:19]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:19][O:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2
Reactant: CC1(C)C(=O)N=C2C1=C(O)C(=O)c1ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COC1=C2C(=NC(=O)C2(C)C)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (compound 1) (0.1 g, 0.415 mmol) in MeOH (5 mL) was added K2CO3 (0.132 g, 0.96 mmol) while stirring at RT. After 10 min. MeI (100 μL, 0.228 g, 1.6 mmol) was added via a syringe and the mixture was allowed to stirred over night. The solvent was removed in vacuum and the solid was dissolved in CHCl3, filtered and purified by prep. HPLC (SF/CHCl3). Yield: 0.051 mg (50%). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 6 H), 3.68 (s, 3 H), 7.58 (t, 1 H), 7.68 (t, 1 H), 8.02 (d, 1 H), 8.23 (d, 1 H). MS (CI) m/z: 256.31 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=3[CH:12]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Clc1ccc(SCCCCBr)cc1Cl
Reactant: O=C1Nc2ccc(O)cc2CO1
Product: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2CO1

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylmercapto)-butylbromide (prepared from 3,4-dichlorothiophenol and 1,4-dibromo-butane, B.p. 0.1 mb : 153°-160° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[C:5]([F:11])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.P(Br)(Br)[Br:26]>C(Cl)Cl>[Br:26][CH2:8][C:7]1[C:2]([F:1])=[C:3]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:4]=[C:5]([F:11])[C:6]=1[F:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(CO)c2F)CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(CBr)c2F)CC1

Procedure:
tert-butyl 4-(2,4,5-trifluoro-3-(hydroxymethyl)phenyl)piperazine-1-carboxylate (180 mg, 0.52 mmol) was reacted under the standard conditions with PBr3 in DCM (see Example 189, Step ii) to give tert-butyl 4-(3-(bromomethyl)-2,4,5-trifluorophenyl)piperazine-1-carboxylate (57 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[C:19]([C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:33][O:34][NH2:35]>CO>[CH3:33][O:34][N:35]=[C:20]([C:19]1[C:14]([O:13][C:10]2[CH:11]=[CH:12][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=O)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C(=O)OC)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A mixture of 2.7 g (7.3 mmol) of methyl [2-(1-(4-chlorophenyl)-3-pyrazolyloxy)pyridin-3-yl]glyoxylate (Example 1a.), 1.16 g of pyridine and 25 ml of methanol were admixed with 0.67 g (8.0 mmol) of O-methylhydroxylamine hydrochloride, and the mixture was stirred at room temperature for 1.5 hours. The resulting precipitate was separated off and washed with ice-cold methanol. The residue was freed from the solvent under reduced pressure. 1.2 g (42%) of the title compound were obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C(N(CC)CC)C.O=[C:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]>C(O)C>[CH2:18]([C:14]1([C:15]([OH:17])=[O:16])[NH:2][CH2:3][CH2:4][S:5]1)[CH3:19]
Reactant: CCC(=O)C(=O)O
Reactant: NCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC1(C(=O)O)NCCS1
Yield: 65.8 %

Procedure:
11.4 g of cysteamine hydrochloride and 10.1 g of triethylamine were dissolved in 100 ml of ethanol, to which was added 10.2 g of 2-keto-butyric acid. The mixture was refluxed for 30 minutes, cooled and filtered thereby giving 10.6 g (yield 65.7%) of 2-ethyl-thiazolidine-2-carboxylic acid with a melting point of 235°-238° C. (decomposed).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:22]2[CH2:21][S:20][CH2:19][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[NH:17][C:16](=[O:27])[C@@H:15]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:14][O:13][C:12](=[O:36])[C:11]=2[CH:10]=[C:9]([N:37]2C(=O)C3[C:39](=CC=CC=3)[C:38]2=[O:47])[CH:8]=1)(C)(C)C.N1C=CC=CC=1>C(OC(=O)C)(=O)C>[C:38]([NH:37][C:9]1[CH:8]=[C:7]([OH:6])[C:22]2[CH2:21][S:20][CH2:19][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[NH:17][C:16](=[O:27])[C@@H:15]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:14][O:13][C:12](=[O:36])[C:11]=2[CH:10]=1)(=[O:47])[CH3:39]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(N3C(=O)c4ccccc4C3=O)cc2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@@H]1CSCc2c(O)cc(NC(C)=O)cc2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
A mixture of 25 mg of the product of Example 159 and 0.1 ml of pyridine in 1.5 ml of acetic anhydride was stirred at 20° C. for 3 hours. The precipitate was collected by filtration, washed with pentane, and dissolved in 1.5 ml of methanol. After the addition of 2.6 mg of potassium carbonate, the mixture was stirred for 1.5 hours at 20° C., and then evaporated in vacuo. Water was added to the residue, and the insoluble material was isolated by filtration, to yield 7 mg of tert-butyl (4R,7S)-12-acetylamino-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-4-methoxycarbonyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:10](=O)([OH:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([O:11][C:10]([N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: c1cc2c(s1)CCNC2
Reactant: CC(C)(C)OC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine (1.3 g, 9.0 mmol) was dissolved in dichloromethane (25 ml), and the solution was mixed with t-butyl bicarbonate (3.1 ml, 13 mmol) and triethylamine (1.3 ml, 9. 0 mmol) and stirred at room temperature for 13 hours. The reaction solution was mixed with dichloromethane, washed with water and saturated brined and dried with anhydrous sodium sulfate. When the solvent was removed by evaporation from the organic layer under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography, it was able to isolate a part of the title compound, but the most part was obtained as its mixture with t-butyl bicarbonate (total yield, 2.3 g).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(O)C>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1cccnc1
Agent: I
Solvent: CCO
Solvent: O
Product: N=C(NCc1cccnc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A mixture of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide, 3.24 g. of 3-(aminomethyl)pyridine and 25 ml. of absolute ethanol is heated under reflux for 24 hours and diluted while hot with 75 ml. of water. After cooling, an oil separates and crystallizes. The mixture is chilled overnight and the crystals are separated and recrystallized from 100 ml. of 50% aqueous ethanol to give the desired product as pale yellow crystals, m.p. 148°-151° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@@:29]([CH:43]4[CH2:46][CH2:45][CH2:44]4)([CH3:42])[C:30]([O:32]CC4C=CC(OC)=CC=4)=[O:31])[CH2:18]3)[CH2:12][CH2:11]2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[N:1]1[CH:2]=[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@@:29]([CH:43]4[CH2:44][CH2:45][CH2:46]4)([CH3:42])[C:30]([OH:32])=[O:31])[CH2:18]3)[CH2:14][CH2:15]2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COc1ccc(COC(=O)[C@@](C)(C2CCC2)N2C[C@H](CN3CCC(c4cnc5ccccn45)CC3)[C@@H](c3cccc(F)c3)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@](C(=O)O)(C1CCC1)N1C[C@H](CN2CCC(c3cnc4ccccn34)CC2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
To 26 mg of α-(R)-(3-(S)-((4-(imidazo[1,2-a]pyridin-3-yl)-piperidine-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-cyclobutylpropanoic acid, 4-methoxy-benzyl ester (from Step C) was added 2 mL of TFA and 0.3 mL of anisole. The reaction was stirred at r.t. for 1 hour. The reaction mixture was concentrated and the residue was purified by flash chromatography with 10% MeOH in CH2Cl2, followed by 15% MeOH and 1% NH4OH in CHCl3 to provide 23 mg of a foamy solid. 1H NMR (500 MHz, CD3OD): δ1.63-1.81 (m, 4H), 1.93-2.15 (m, 5H), 2.33(t, J=15.6 Hz, 2H), 2.44(m, 1H), 2.86(m, 1H), 3.00(d, J=13.8 Hz, 1H), 3.15-3.89(m, 13H), 7.11 (m, 1H), 7.28 (m, 2H), 7.39-7.48 (m, 2H), 7.75 (s, 1H), 7.85 (m, 2H) 8.32 (d, J=6.9 Hz, 1H). ESI-MS 505 (M+H); BLC A 1.64 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[CH:3][C:4]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2ccc(F)cc2)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.4 mg (0.03 mmol) of (4-fluorophenyl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]3[CH:15]=2)[CH2:28][CH2:29]1
Reactant: FC(F)(F)c1ccc2nc(CCl)cn2c1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Yield: 77.4 %

Procedure:
A mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (0.452 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.468 g), diisopropylethylamine (Aldrich; 0.299 g), and THF (4 mL) is stirred at reflux for 21 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel using methanol/dichloromethane (2.5/97.5) to give 0.64 g of 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine. The methanesulfonate salt is prepared by dissolving 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine in ethyl acetate/hexane and adding methanesulfonic acid (0.143 g) dissolved in methanol. The mixture is concentrated under reduced pressure and the residue is crystallized from ethyl acetate to give 0.691 g of the title compound; mp 161-162° C.; MS m/z 428; IR (mineral oil) 1162, 1225, 1033, 1130, 1142, 1337 cm-1. 1H NMR (CDCl3) δ 2.78, 3.09, 3.83, 6.96, 7.18, 7.31, 7.35, 7.66, 7.68, 8.47.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=2)[C@H:30]([OH:41])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:35]=2)[C@H:30]([OH:41])[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(N)c2)[C@H](O)C1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)[C@H](O)C1

Procedure:
186 d) (±)-(cis)-3-Hydroxy-4-{3-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (270.0 mg, 0.8773 mmol) and (±)-(cis)-4-(3-amino-phenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (286.0 mg, 0.9782 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (77.0 mg, 0.141 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.313 g, 63%). MP=166-170° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.23 (d, J=7.8 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.66 (d, J=7.5 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.03 (t, J=6.8 Hz, 1H), 6.96-6.90 (m, 2H), 4.35 (br s, 2H), 4.02 (br s, 1H), 3.11 (s, 3H), 3.08-3.00 (m, 1H), 2.90-2.80 (m, 2H), 2.36-2.24 (m, 1H), 1.72-1.60 (m, 2H), 1.50 (s, 9H). MS=586 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(Cl)cnc3[nH]c(-c4ccc(OCCN5CCOCC5)cc4)nc23)cc1
Temperature: 100 °C
Yield: 32.6 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.050 g, 0.13 mmol), 4-methylphenylboronic acid (0.027 g, 0.19 mmol), K2CO3 (0.097 g, 0.70 mmol) and Pd(PPh3)4 (0.029 g, 0.025 mmol) were mixed in a vial. Dioxane (3 ml) was added and the reaction mixture was heated to 100° C. under argon for 4 h. EtOAc (50 ml) was added and the solution was washed with water. Drying (Na2SO4) and evaporation gave crude material which was purified by column chromatography (dichloromethane/methanol, 95:5), giving the title product (0.019 g, 33%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:10]1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH2:44]>C(Cl)Cl>[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH:44][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: Cc1ccccc1NN
Reactant: CCCCCCCCC1CC1CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)NNc1ccccc1C
Reaction time: 2 h

Procedure:
To a solution of 3.0 g of dihydrosterculic acid* in 75 ml methylene chloride cooled to -20°, is added dropwise 1.1 g triethyl amine and then dropwise 1.1 g ethyl chloroformate. The reaction mixture is allowed gradually to come to room temperature and stirred for 2 hours. There is then added 1.0 g triethylamine followed by 1.6 g o-methylphenyl hydrazine hydrochloride and the reaction mixture then stirred for 16 hours. Thereafter the reaction mixture is extracted five times with portions of 2 N hydrochloric acid, then once with 2 N aqueous sodium hydroxide and washed extensively with saturated aqueous sodium chloride. The organic phase is then dried over anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness to obtain a residue. The residue is then chromatographed over silica gel, with chloroform as the eluent. The desired fractions** are combined and evaporated i.v. to dryness to yield the title product as a waxy solid, NMR; b +0.65(3), b -0.3(1), d 8.0(1), d 6.1(1), s 2.1(3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7](=O)[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH3:8]
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)C1COCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNC(C)C2COCCO2)cc1
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a solution of 1-(1,4-dioxan-2-yl)ethanone (12 g, 92.2 mmol) in 1,2-dichloroethane (100 mL) was added (4-methoxyphenyl)methanamine (25 g, 184.4 mmol) at room temperature. The mixture was allowed to stir for 3 hours, and then sodium triacetoxyborohydride (39 g, 184.4 mmol) was added. The resulting mixture was allowed to stir for 48 hours at room temperature. The reaction mixture was quenched by adding water, extracted with dichloromethane (100 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel (elute: dichloromethane/methanol 100:1→50:1→20:1) to give 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (16.4 g, 71%) as a yellow solid. LCMS (M+H+) m/z: calcd. 251.15. found 251.9. To a solution of 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (5 g, 19.9 mmol) in anhydrous methanol (100 mL) was added palladium 10% on carbon (240 mg, 2 mmol), then purged with hydrogen (30 psi), the mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to afford the title compound (2.5 g, 96%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][NH:14][C:15]([NH2:17])=[S:16])[C:9](=NO)[CH3:10])=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[N:14][C:15]([S:16][CH3:18])=[N:17][C:9]=2[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=NO)C(=NNC(N)=S)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CSc1nnc(-c2ccc(Cl)cc2)c(C)n1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A mixture of 4'-chloro-2-hydroxyiminopropiophenone thiosemicarbazone (113.21 g), potassium carbonate (128.71 g) and water (990 ml) was refluxed for 25 hours with stirring, and the reaction mixture was treated with activated charcoal and filtered by suction. To the filtrate was added dropwise methyl iodide (76 g) with stirring, and the stirring was continued for 15 minutes at room temperature. The resulting solid was collected by filtration, washed with water and dissolved in chloroform. The solution was treated with silica gel and filtered, and the filtrate was evaporated under reduced pressure. The residue was washed with diisopropyl ether and dried to give a solid of 6-(4-chlorophenyl)-5-methyl-3-methylthio-1,2,4-triazine (61.1 g).
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>ClCCl>[C:41]([N:10]1[CH2:11][CH:1]2[CH2:13][CH2:12][CH:8]([C:7]3[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=3)[CH2:9]1)(=[O:43])[CH3:42]
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc12
Reaction time: 0.5 h

Procedure:
N-{(1R,2R)-2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (35 mg, 0.0713 mmol) was placed in dichloromethane (3 mL) and triethylamine (21.6 mg, 0.214 mmol, 30.0 μL, 3.0 eq) was added followed by acetyl chloride (6.67 mg, 0.0856 mmol, 6.04 μL, 1.2 eq). The reaction was stirred for 30 minutes and then concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-6% MeOH/CH2Cl2 as the eluting solvent to obtain N-{(1R,2R)-2-[2-(10-acetyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a white foam as a mixture of diastereomers (32.88 mg, 86%). LCMS (m/e) 533 (M+1); 1H-NMR (CDCl3, 400 MHz) mixture of diasteromers δ 7.90 (s, 1H), 7.50-7.23 (m, 1H), 7.20-6.80 (m, 2H), 5.80-5.40 (m, 2H), 4.38-4.07 (m, 1H), 4.00-3.70 (m, 2H), 3.70-3.52 (m, 1H), 3.50-3.30 (m, 1H), 3.30-3.00 (m, 4H), 2.79 (s, 3H), 2.30-1.20 (m, 14H).