Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:27][CH2:26][CH:25]([C:19]4[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1ccc(C2CCNCC2)cc1OC
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1OC

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3,4-dimethoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 82% overall yield. FDMS m/e=410 (M+ of free base). α[D]589 =-11.84 (c=0.46, methanol).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH2:6][C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=2)[CH2:3]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:26]([N:22]1[CH:21]=[C:20]2[C:24]([CH:25]=[C:17]([C:9]3[CH:8]=[C:7]([CH2:6][CH:4]4[CH2:5][N:2]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:3]4)[N:15]4[C:10]=3[C:11]([NH2:16])=[N:12][CH:13]=[N:14]4)[CH:18]=[CH:19]2)=[N:23]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 17.7 %

Procedure:
To a solution 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.22 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (19 μL, 0.25 mmol) and N,N-diisopropylethylamine (117 μL, 0.67 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (17%) of the desired product. 1H NMR (400 MHz, DMSO-da) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.25-7.37 (m, 5 H), 7.13 (dd, 1 H), 6.66 (s, 1 H), 5.64 (s, 2 H), 3.97 (t, 2 H), 3.69 (dd, 2 H), 3.14-3.19 (m, 2 H), 2.97-3.98 (m, 1 H), 2.96 (s, 3 H); ES-MS m/z 5488.38 [M+H]+, HPLC RT (min) 2.98.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1.[OH-:15].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([OH:15])[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1
Reactant: [OH-]
Reactant: CCc1nc2cc(Cl)nc(SC)n2n1
Agent: [K+]
Product: CCc1nc2cc(Cl)nc(O)n2n1

Procedure:
In analogy to Example 33A, 242 mg (99% of theory) of the product are obtained from 280 mg (1.22 mmol) of 7-chloro-2-ethyl-5-(methylsulphanyl)[1,2,4]triazolo[1,5-c]pyrimidine (Example 101A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[NH2:13][C:14]1[CH:34]=[CH:33][C:17]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=1>CO>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=4)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:33][CH:34]=2)=[N:3][N:4]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4c3CCCC4)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A slurry of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (1.66 g, 8.18 mmol) and 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (2.00 g, 6.82 mmol) in 14 mL 2-BuOH was heated in a sealed pressure vessel to 110° C. The reaction became a thick mass that eventually became a stirring suspension over about 30 min. After 4 h, the reaction was cooled to ambient temperature, and the material was partitioned between 2N NaOH and EtOAc. The aqueous layer was extracted once with EtOAc. The organic layers were dried over anhyd. sodium sulfate, filtered, and concentrated to yield a brown solid. This solid was dissolved in MeOH/MC and adsorbed onto 10 g silica gel, dried, and purified by chromatography (0-100% EtOAc/DCM) to give 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine as an off-white solid. MS m/z=460 [M+H]+. Calc'd for C24H22ClN7O: 459.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:16](O)=O.C=O.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=CO
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
4-Fluorophenyl piperidin-4-yl methanone 1.79 g (8.66 mmol) was added to formic acid (1.5 ml) and formaldehyde 1.05 ml and the reaction mixture was stirred at 55-60° C. for 3 hours. After cooled down, water was added, basified with potassium hydroxide pellets to pH>10 and extracted with ethyl ether 3×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1.88 g of desired product in 98% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NS(C)(=O)=O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
{4′-Amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.080 g, 0.2 mmol), methanesulfonyl chloride (0.04 mL, 0.3 mmol), and triethylamine were reacted in CH2Cl2 to give {2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4′-methanesulfonylamino-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester. {2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-methanesulfonylamino-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.2 mmol) was hydrolyzed with lithium hydroxide to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:17][CH2:16][C:15]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]4=[O:26])[CH2:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[CH3:30][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2([CH2:16][CH2:17][N:13]([C:10]3[N:11]=[N:12][C:7]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[N:6]=4)=[CH:8][CH:9]=3)[CH2:14]2)[C:18]1=[O:26]
Reactant: CI
Reactant: Cc1noc(-c2ccc(N3CCC4(C3)C(=O)Nc3ccccc34)nn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(N3CCC4(C3)C(=O)N(C)c3ccccc34)nn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
1′-[6-(3-Methyl-1,2,4-oxadiazol-5-yl)pyridazin-3-yl]spiro[indole-3,3′-pyrrolidin]-2(1H)-one (300 mg) obtained in Example 158 was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (60 w %, 35 mg) was added, and the mixture was stirred at room temperature for 30 min. Iodomethane (0.054 mL) was added, and the mixture was further stirred at room temperature for 3 hr. The reaction was quenched with saturated aqueous ammonium chloride solution, and water (20 mL) was added. The resulting precipitate was collected by filtration to give the object product (198 mg, 64%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>CN1C(=O)CCC1>[Cl:8][C:7]1[C:2]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[CH:3][C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=1
Reactant: CN1CCC(N)CC1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Solvent: CN1CCCC1=O
Product: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Cl)CC1
Yield: 73 %

Procedure:
A solution of N-(4,5-dichloropyridin-2-yl)pivalamide (0.400 g, 1.62 mmol), N-methyl-4-aminopiperidine (0.185 g, 1.62 mmol) in NMP (3 mL) was heated at 220° C. under microwave irradiation for 3 h. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (2 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.384 g, 73%).
Reaction SMILES: [CH3:1][S:2]SC.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH:10]([SH:14])[CH:11]([CH3:13])[CH3:12]>>[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH:10]([S:14][S:2][CH3:1])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C(S)c1nccs1
Reactant: CSSC
Product: CSSC(c1nccs1)C(C)C

Procedure:
According to the same procedure, from dimethyldisulphide and 1-(2-thiazolyl)-2-methylpropyl-mercaptan there is obtained [1-(2-thiazolyl)-2-methylpropyl]-methyl-disulphide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])[CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CSc2cccc[n+]2[O-])c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(CS(=O)c2cccc[n+]2[O-])c1

Procedure:
The procedure employed is identical with that of Example 68 using 4.6 gm (0.02 mol) 2-(3-Methylphenylmethylthio)pyridine N-oxide in 50 ml of chloroform and 4 gm (0.02 mol) MCPBA in 100 ml chloroform.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Cl)ccc1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (3.5 g, 11 mmol) and N-tert-Butyl-4-chloro-2-methyl-benzamide (7.3 g, 32 mmol) followed by purification using silica gel flash column chromatography gives the title compound.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][N:6]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4][C:3]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)(C)C>[NH2:18][C:16]1[S:17][C:3]2[CH2:4][CH2:5][N:6]([C:9]([CH:11]3[CH2:13][CH2:12]3)=[O:10])[CH2:7][CH2:8][C:2]=2[N:15]=1
Reactant: O=C1CCN(C(=O)C2CC2)CCC1Br
Reactant: NC(N)=S
Solvent: CC(C)O
Product: Nc1nc2c(s1)CCN(C(=O)C1CC1)CC2
Yield: 11.4 %

Procedure:
A suspension of 5-Bromo-1-cyclopropanecarbonyl-azepan-4-one (3.87 grams, 14.8 mmol, obtained in above step) and thiourea (1.13 grams, 14.8 mmol) in isopropanol (40 mL) was refluxed for 6 hours. After completion of reaction, reaction mass was concentrated and the residue obtained was purified by flash chromatography (methanol/chloroform, 3/97) to obtain the title compound (0.4 grams).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:21])=[C:11]([C:17]([O:19][CH3:20])=[O:18])[N:12]=[C:13]2I)=[CH:8][CH:7]=1.[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[C:25]([C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)[CH:15]=2)[C:10]([OH:21])=[C:11]([C:17]([O:19][CH3:20])=[O:18])[N:12]=1)#[N:26]
Reactant: COC(=O)c1nc(I)c2cc(Oc3cccc(F)c3)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Methyl 7-(3-fluorophenoxy)-4-hydroxy-1-iodoisoquinoline-3-carboxylate (100 mg, 0.23 mmol) and CuCN (41 mg, 0.46 mmol) were suspended in DMF (1.0 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 67 mg. MS: (−) m/z 337.25 (M−1).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:17]1[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]([CH:10]1[CH2:11][CH2:12][N:13]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:14][CH2:15]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: Cc1cncc(Cl)n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1cncc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)n1
Yield: 47 %

Procedure:
KOBut (483 mg, 4.32 mmol, 2.5 eq) was added at room temperature to a solution of tert-butyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-60) (370 mg, 1.72 mmol, 1 eq) and 2-chloro-6-methylpyrazine (244 mg, 1.9 mmol, 1.1 eq) in toluene (50 ml) and the mixture was degassed for 30 min with argon. BINAP (64.5 mg, 0.103 mmol, 0.06 eq) and Pd2(dba)3 (31.6 mg, 0.034 mmol, 0.02 eq) were added and the reaction mixture was refluxed for 16 h. After cooling, concentration under reduced pressure was carried out. The residue was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml) and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure and the crude product so obtained was purified by column chromatography (Alox, 0.5% methanol/dichloromethane). The desired product was in the form of a brown solid. Yield: 47% (250 mg, 0.816 mmol)
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:23]([CH2:2][C:3]2[O:4][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:6][C:7]=2[CH2:8][OH:10])[CH3:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Reactant: CNC1CCCCC1
Product: CN(Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO)C1CCCCC1

Procedure:
Prepared using intermediate 44 and N-methylcyclohexylamine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[C:19]([Cl:21])[C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([Cl:22])[CH:4]=1.[CH3:23][C:24]1[N:29]=[C:28]2[N:30]=[C:31]([CH2:33][CH3:34])[NH:32][C:27]2=[C:26]([CH3:35])[CH:25]=1>>[C:9]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:7][C:6]1[C:19]([Cl:21])=[CH:20][C:3]([CH2:2][N:30]2[C:28]3=[N:29][C:24]([CH3:23])=[CH:25][C:26]([CH3:35])=[C:27]3[N:32]=[C:31]2[CH2:33][CH3:34])=[CH:4][C:5]=1[Cl:22])([O:11][CH3:12])=[O:10]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: COC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cc(Cl)c(OC(C(=O)OC)c2ccccc2)c(Cl)c1
Yield: 66.4 %

Procedure:
The product of Step E (0.126 g, 0.31 mmol) was used to alkylate 0.050 g (0.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine according to the procedure described for Step B of Example 2, which after purification afforded 0.096 g (68%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10].C(N(CC)CC)C.[C:29]1([C:35](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 59.2 %

Procedure:
To a solution of 5-amino-4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methylpyrazole (597 mg) and triethylamine (243 mg) in methylene chloride (10 ml) was added triphenylmethyl chloride (669 mg), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate to give 4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methyl-5-triphenylmethylaminopyrazole (640 mg) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:38][CH2:39][O:40][CH3:41])=[C:14]([CH:37]=1)[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16]>CC(C)=O>[CH3:41][O:40][CH2:39][O:38][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[O:16]
Reactant: CN1CCNCC1
Reactant: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: COCOc1ccc(CN2CCN(C)CC2)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, 1-methylpiperazine (0.16 mL) was added to an acetone (2.3 mL) suspension of tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.15 g), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a 1.0 mol/L aqueous solution of sodium hydroxide and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain 0.14 g of tert-butyl 2-(2-(methoxymethoxy)-5-((4-methylpiperazin-1-yl)methyl)benzamido)-4-phenylbenzoate as a yellow oil substance.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[OH-].[Na+].CN1CCC[C:31]1=[O:35]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:5]([CH2:31][OH:35])=[C:4]([CH2:3][CH3:2])[N:6]=2)=[N:10]1
Reactant: CN1CCCC1=O
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)oc1CO
Yield: 60 %

Procedure:
730 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (1.86 mmol) and 3.75 ml of NaOH, 1N (3.75 mmol) were stirred in 7.4 ml of N-methylpyrrolidone at 50° C. under argon overnight. After cooling, the mixture was poured onto ice-water and the product which had precipitated out was filtered off and dried. Finally, it was purified by column chromatography (SiO2, cyclohexane:ethyl acetate 2:1). 375 mg (60%) of 2-[1-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-ethyl-oxazole were obtained as white crystals.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[C:8]([CH:10]([CH3:19])[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])#[N:9]>C(Cl)Cl>[CH2:1]([NH:5][C:6]([N:12]([CH2:11][CH:10]([C:8]#[N:9])[CH3:19])[CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C#N)CNCCCN(C)C
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)N(CCCN(C)C)CC(C)C#N

Procedure:
Under nitrogen, a solution of 99.1 g of butyl isocyanate in 100 ml of methylene chloride is added dropwise in the course of 1 hour to a solution of 169.3 g of N-(β-cyanopropyl)-dimethylaminopropylamine in 500 ml of methylene chloride. The mixture is then refluxed for 2 hours, concentrated, and the residue is treated at 80° C. in a high vacuum in order to remove all low boiling constituents. Yield: 249.2 g (90.8%) of product in the form of an oil. Titration: 1 equivalent=261.9 g (theory 268.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[N:18]([CH3:37])[CH:19]=[C:20]([CH2:24][C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[N:27][CH:26]=4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a solution of 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (300 mg, 0.561 mmol) and DIPEA (0.294 mL, 1.682 mmol) in DCM (15 mL) was added MeI (0.053 ml, 0.841 mmol). The mixture was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (100 mg, 32.5% yield). LCMS: rt=3.49 min, [M+H+]=549