Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[C:14]1([NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>C(O)C>[C:14]1([NH:20][C:21](=[O:25])[C:22]([C:23]#[N:24])=[CH:12][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[C:11]3[C:6]=2[CH:7]=[CH:8][CH:9]=[N:10]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: O=Cc1ccc(O)c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccc(O)c2ncccc12)C(=O)Nc1ccccc1
Yield: 75 %

Procedure:
A solution of 8-hydroxy-5-quinolinecarboxaldehyde (1.732 g, 0.010 mol), N-phenyl cyanoacetamide (1.602 g, 0.010 mol) and piperidine (0.255 g, 0.003 mol) in absolute ethanol (50 ml) was heated for 3 h at reflux. The reaction mixture was chilled to about 10°-15° C., the precipitate filtered, the residue washed with ice-cooled ethanol and dried under vacuum. Almost pure title compound was obtained in about 75% yield (2.365 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5].[NH4+].[OH-].[NH2:26]C1C=C(F)C([N+]([O-])=O)=CC=1C(NC1C=C2C(C=NN2)=CC=1)=O>O1CCOCC1.O>[NH2:26][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]([C:4]([NH:6][C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[O:5])=[C:2]([Cl:1])[CH:19]=1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
A solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (2 mmol) in dioxane (4 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, the volatiles were removed in vacuo. The residue obtained was suspended in cold water with stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:24](=[O:25])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19](=[O:20])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1c1ccccc1

Procedure:
To a suspension of 100 g (666 mmol) of benzylurea and 156.8 g (666 mmol) of diethyl phenylmalonate in 340 ml of methanol, 164 ml (666 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 163.23 g (83.3%, white crystal) of the desired product.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24](COC3C=CC=CC=3)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H]([CH2:48][O:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)CC2)CCCCC1.C([O:60][C:61](=[O:71])[CH:62](SC1SC(N)=NC=1)[CH3:63])C>>[CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:57][O:56][C:53]3[CH:52]=[CH:51][C:50]([O:49][CH3:48])=[CH:55][CH:54]=3)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:63][CH2:62][C:61]([OH:71])=[O:60])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(OC[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Product: COc1ccc(OC[C@H]2CC[C@H](N(C(=O)Nc3ncc(SCCC(=O)O)s3)C3CCCCC3)CC2)cc1

Procedure:
Prepared in an similar manner to {2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-[trans-4-(4-methoxy-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:33][CH2:34][O:35]C)[N:18]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl.C(#N)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:33][CH2:34][OH:35])[N:18]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Agent: BrB(Br)Br
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCCn2c(CCO)nc3c(N)nc4ccccc4c32)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Boron tribromide (5.50 mL of 1 M in dichloromethane) was added dropwise to a chilled (0° C.) suspension of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide (1.0 g, 2.2 mmol; U.S. Pat. No. 6,677,349, Example 253) in dichloromethane (20 mL). The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with methanol. Hydrochloric acid (about 10 mL of 6 N) was added and the mixture was stirred at 50° C. overnight. The mixture was diluted with water (50 mL) and ethyl acetate (100 mL) and then brought to neutral pH with solid sodium hydroxide. The layers were separated and the aqueous was extracted with ethyl acetate (×2). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide a white solid. This material was suspended in hot acetonitrile, allowed to cool, and then the solvent was decanted. The resulting material was dried under vacuum to provide about 200 mg of N-{3-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide as a white solid, m.p. 231-232° C. Anal, calcd for C22H25N5O3S.0.20 CH4O: % C, 59.79; % H, 5.85; % N, 15.70. Found: % C, 59.44; % H, 5.89; % N, 15.52.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:11][N:12]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: CNCCN1CCOCC1
Reactant: Clc1noc2ccccc12
Product: CN(CCN1CCOCC1)c1noc2ccccc12
Temperature: 140 °C
Yield: 23.5 %

Procedure:
To a sealed tube was added 3-chloro-1,2-benzisoxazole (3.0 g) and N-methyl-N-[2-(4-morpholinyl)ethyl]-amine (12.7 g). The reaction was heated to 140° C. over 72 hours and then cooled to room temperature. The residue was partitioned between EtOAc and water, extracted again with EtOAc, and the organic phase was dried over MgSO4 and concentrated in vacuo. Hash column chromatography (silica gel) eluting with 1-3% MeOH/DCM provided the product (1.2 g), as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:17].[CH2:9]([C:11]1[N:16]=[C:15]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1)[CH3:10]
Reactant: CCc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Reactant: Cc1ccccc1N
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2)nc(Nc2ccccc2C)n1
Product: Cl
Yield: 23.6 %

Procedure:
After 2-methylaniline(0.55 ml, 5.15 mmol) was added to a mixture solution of 6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine(0.7 g, 2.56 mmol) and dimethylformamide(5 ml), 0.23 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]([CH3:25])([CH3:24])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C(=O)C)[CH:8]=1.[OH-].[K+].C(O)C.C(OCC)(=O)C>O>[F:26][CH:2]([F:1])[C:3]([CH3:24])([CH3:25])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1
Reactant: CC(=O)N(c1ccccc1)c1cc(COCC(C)(C)C(F)F)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(COCc1ccc(F)c(Nc2ccccc2)c1)C(F)F
Reaction time: 8 h
Yield: 52 %

Procedure:
1,1-Difluoro-2,2-dimethyl-3-[3-(N-phenyl-N-acetylamino)-4fluorobenzyloxy]propane (0.5 g) was suspended in a 1 molar solution of potassium hydroxide in water containing 20% by volume ethanol and the mixture was heated at the reflux temperature for 8 hours. After standing overnight at the ambient temperature, the mixture was shaken several times with ethyl acetate and the combined organic extracts washed with water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a brown oil which was purified by column chromatography on a silica gel supoort, eluting with petroleum ether (boiling range 40°-60° C.) containing 10% by volume ethyl acetate, to give the title compound (0.23 g) as a pale yellow oil.
Reaction SMILES: O[CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5].S(Cl)([Cl:14])=O>>[Cl:14][CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5]
Reactant: CC(=O)NC(O)C(Cl)(Cl)CCl
Reactant: O=S(Cl)Cl
Product: CC(=O)NC(Cl)C(Cl)(Cl)CCl

Procedure:
30 ml of thionyl chloride were poured over 15 gm of N-(1-hydroxy-2,2,3-trichloro-n-propyl)-acetamide, and the mixture was refluxed until the solution became clear. Subsequently, the excess thionyl chloride was distilled off in vacuo, and the residue was recrystallized from benzene/petroleum ether. Upon washing of the crystallizate with petroleum ether, a colorless substance was obtained. Yield: 13.5 gm; m.p. 70°-72° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=[CH2:24])[C:11]1=[O:25])=[O:4].B1C2CCCC1CCC2.[OH-:41].[Na+].OO>C1COCC1.CCO>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[C:11](=[O:25])[C@@H:12]([CH2:22][CH2:23][CH2:24][OH:41])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1.[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[C:11](=[O:25])[C@H:12]([CH2:22][CH2:23][CH2:24][OH:41])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC[C@H]1OCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@H](CCCO)OC[C@H]2C2CCCCC2)c(C(=O)O)s1
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@H](CCCO)OC[C@H]2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-((R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (200 mg, 0.45 mmol, 1.0 equiv) in THF (4.0 mL) at 0° C. was added 9-BBN (2.2 mL, 0.5 M in THF, 1.1 mmol, 2.5 equiv) over 10 minutes and the resulting solution was stirred at room temperature for 18 hours. The solution was then cooled to 0° C. and to the solution was added EtOH, aq. NaOH. solution, aq. H2O2 solution. The reaction mixture was heated to reflux for 90 minutes. After cooled to room temperature, the reaction mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and the residue was purified by prep-HPLC to give product 3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (20 mg) and 3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (20 mg). The stereochemistry at 2 position of morpholinone has not been established. Product 1: MW: 448.3 [M+H]+. 1H-NMR (400 MHz, CD3OD): δ 6.93 (s, 1H), 4.14 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.58 (m, 2H), 2.02-1.48 (m, 10H), 1.32 (s, 9H), 1.25-1.17 (m, 6H). Product 2: MW: 448.3 [M+H]+. 1H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 4.13 (m, 1H), 3.90 (m, 1H), 3.82 (m, 1H), 3.57 (m, 2H), 1.97-1.48 (m, 10H), 1.32 (s, 9H), 1.26-1.09 (m, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C=O.[BH3-][C:37]#N.[Na+]>CO.CC(O)=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([CH3:37])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C)CC4)n3)cc2)CC1
Reaction time: 20 h
Yield: 77.9 %

Procedure:
To a solution of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (25 mg, 0.055 mmol) and 37% aq. CH2O (0.020 mL, 0.27 mmol) in MeOH (1 mL) and CH3CO2H (0.1 mL) at room temperature, NaBH3CN (23 mg, 0.36 mmol) was added. The solution was stirred for 20 h. The mixture was then purified by HPLC to give the titled compound (20 mg). MS 467.46 (M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:19]([OH:21])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]([C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=1)[NH2:23].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:19]([NH:23][NH:22][C:24]2[N:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][N:25]=2)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: O=CN(CC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cyclohexanecarboxylic acid (0.10 g, 0.34 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.06 g, 0.34 mmol), NMM (0.17 g, 1.7 mmol) and HOAt (0.046 g, 0.34 mmol) in DMF (2 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.067 g, 0.34 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.070 g, 47%). MH+452.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:4])[CH3:3].[CH3:11]O.C=O.[C:15](=[O:18])([O-])[O-].[K+].[K+]>>[CH3:11][O:18][CH2:15][N:5]([CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CO
Reactant: CC(C)(C)NC[Si](C)(C)C
Agent: C=O
Agent: [K+]
Product: COCN(C[Si](C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Methyl-N-[(trimethylsilyl)methyl]propan-2-amine (from preparation 5) (4.31 g, 27 mmol) was added to an ice-cooled mixture of methanol (1.29 mL, 31.8 mmol) and aqueous formaldehyde (37% w/v 2.49 mL, 33 mmol) over 45 minutes. The heterogeneous mixture was stirred at 0° C. for 2 hours and then solid potassium carbonate (325 mesh) (1.08 g, 13 mmol) was added and the mixture stirred for 30 minutes at 0° C. The layers were separated and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give an 80:20 mixture of the title compound and unreacted tert-butyl[(trimethylsilyl)methyl]amine as a colourless oil (5.09 g). The mixture was used directly without further purification in preparation 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[C:23]1([CH2:29][CH:30]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:32]>>[ClH:1].[ClH:32].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Reactant: O=CCc1ccccc1
Agent: Cl
Product: OC1(C(CN2CCN(CCc3ccccc3)CC2)c2cccc(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 117,1-{1-(3-chlorophenyl)-2-[4-(2-phenylethyl)piperazin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 1) and phenylacetaldehyde. MS (ESI) m/z 427/429 ([M+H]+); HRMS: calcd for C26H35ClN2O.2.00 HCl, 498.1971; found (ESI), 427.2505.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].[CH2:21]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][C:26]=1[O:33][CH3:34])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([CH2:31][N:18]2[CH2:17][CH2:16][CH:15]([C:8]3[C:9]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=3)[CH2:20][CH2:19]2)[CH:28]=[CH:27][C:26]=1[O:33][CH3:34])[CH3:22]
Reactant: CCOCCn1cc(C2CCNCC2)c2cccnc21
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: CCOCCn1cc(C2CCN(Cc3ccc(OC)c(C(=O)OCC)c3)CC2)c2cccnc21

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 0.73 g (2.67 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.88 g (3.20 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. After standard work-up and purification, 0.38 g (31% of yield) of the expected product were obtained.
Reaction SMILES: CS[C:3]1[C:4]2[NH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:12])[N:11]=1.[NH2:22][NH2:23]>O>[CH2:13]([N:9]1[C:8]2[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[NH:5][C:4]=2/[C:3](=[N:22]\[NH2:23])/[NH:11][C:10]1=[O:12])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NN
Reactant: CCCCCn1c(=O)nc(SC)c2[nH]c(C(F)(F)F)nc21
Solvent: O
Product: CCCCCn1c(=O)[nH]/c(=N/N)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C

Procedure:
A mixture of 6-(methylthio)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-2H-purin-2-one (0.15 g, 0.23 mmol) and hydrazine (0.80 mL, 25 mmol) in water (0.80 mL) was heated at 100° C. for 1 h. The solution was concentrated under reduced pressure and azeotropically treated with toluene twice. The resulting residue was used for next step without purification. LCMS calculated for C11H16F3N6O (M+H): 305.1; found: 305.1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[NH:20][C:19]([C:21]3[N:26]=[CH:25][C:24]([CH:27]([OH:29])[CH3:28])=[CH:23][CH:22]=3)=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11](SC)=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCC[CH2:31]1.O.O[O:37][S:38]([O-:40])=O.[K+]>C(OCC)(=O)C.CO>[CH:1]1([CH2:6][CH:7]([C:16]2[NH:20][C:19]([C:21]3[N:26]=[CH:25][C:24]([CH:27]([OH:29])[CH3:28])=[CH:23][CH:22]=3)=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:38]([CH3:31])(=[O:40])=[O:37])=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C(CC2CCCC2)c2ccc(-c3ccc(C(C)O)cn3)[nH]2)nc1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(-c2ccc(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cn3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a mixture of 1-[6-(5-{2-cyclopentyl-1-[5-(methylsulfanyl)pyridin-2-yl]ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]ethanol (313 mg), tetrahydrofuran (5.5 mL), water (5.5 mL) and methanol (5.5 mL) was added Oxone (registered trademark) (566 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (128 mg, yield 38%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 440 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)#[N:40].C([O-])([O-])=O.[K+].[K+]>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:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([C:39]#[N:40])[CH:46]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: N#Cc1cccc(B(O)O)c1
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+]
Product: Cc1cc2nc(-c3ccnc(-c4cccc(C#N)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (19.7 mg, 0.034 mmol), 3-cyanophenylboronic acid (6.1 mg, 0.041 mmol), Pd(PPh3)4, and K2CO3 (14.3 mg, 0.103 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (0.4 mL) and degassed water (0.1 mL). The reaction mixture was heated at 110° C. for 1.5 h, cooled, diluted with ethyl acetate, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+: calc'd for C37H37ClN3O3S: 638.2 (M+H+); Found: 637.9 (M+H+).