Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].O1CCCCC1[O:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16]Cl>CS(C)=O.[Cl-].[Na+].O>[C:1]([CH2:16][CH2:15][CH2:14][C:13]#[C:12][CH2:11][OH:10])#[N:2]
Reactant: [C-]#N
Reactant: ClCCCC#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCC#CCO
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a stirred slurry of sodium cyanide (15 g, 306 mmol) in dimethyl sulphoxide (100 ml) preheated to 85° C., was added 1-tetrahydropyranyloxy-6-chloro-hex-2-yne (66.2 g, 306 mmol) at such a rate as to keep the temperature between 85° C. and 100° C. One hour after the addition was completed, the cooled mixture was slowly added to brine (600 ml) and extracted with ether (3×200 ml). The combined ether extracts were washed with further brine (200 ml) and dried over sodium sulphate. After removal of the solvent under reduced pressure, the reddish-brown oil was distilled and the fraction boiling between 140° and 160° C. (0.25 m.m.) collected and dissolved in methanol (200 ml). This solution was stirred overnight with 5 MH2SO4 (30 ml) and neutralised with solid potassium carbonate. The methanol was removed under reduced pressure and the residue partitioned between ether (200 ml) and brine (300 ml). The aqueous layer was extracted with further ether (2×300 ml). The combined organic extracts were washed with brine (2×100 ml) and dried over sodium sulphate. Removal of the solvent under reduced pressure, and distillation of the oil obtained gave 6-cyano-hex-2-yn-1-ol (22.0 g, 58%) as a colourless oil.
Reaction SMILES: CN.O.[C:4]1([CH:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]2[CH2:14][CH:13]([N:15]3C(=O)C4=CC=CC=C4C3=O)[CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[NH2:15][CH:13]1[CH2:14][N:11]([CH:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN
Solvent: O
Solvent: CCO
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
572 ml of 40% aqueous methylamine solution and 300 ml of water were added successively to a suspension of 78.0 g (0.212 mol) of 1-(diphenylmethyl)-3-(phthalimido)-azetidine in 480 ml of ethanol. After 7 days' stirring at ambient temperature a clear solution had formed, which was freed from excess methylamine and ethanol in vacuo. The aqueous solution remaining was extracted exhaustively with ethyl acetate. The ethyl acetate extracts were dried over sodium sulphate and dried in vacuo. 45.0 g (89% of theoretical) of a colourless oil were obtained, which was further processed without any additional purification.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[C:45]2[N:44]=[CH:43][N:42]([CH3:46])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[C:45]3[N:44]=[CH:43][N:42]([CH3:46])[C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: Cn1cnc2c(CCl)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2ncn3C)cc1

Procedure:
Analogously to Method D, 0.800 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.317 g of 4-chloromethyl-1-methyl-1H-benzimidazole are reacted. The title compound is obtained as a yellow resin. Rf=0.30 (15:1 dichloromethane-methanol); Rt=4.74.
Reaction SMILES: [Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:42])[C@:16]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:32])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3].[C:43]([N:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52](O)=[O:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].Cl.CN(C)CCCN=C=NCC>ClCCl>[Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:42])[C@:16]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:52]([C@@H:51]5[CH2:55][CH2:56][CH2:57][N:50]5[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:53])=[C:26]([CH3:32])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a solution of 3 g of 3,5-dimethyl-4-hydroxybenzyl bromide in CH3CN(30 mL) was added 1.2 g of (1R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]thiazol-4-yl]benzonitrile and stirring was continued for 2 h at room temperature. The precipitate was filtered and washed with ether to give 1.37 g(81 %y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxy)benzyl-1H-[1,2,4]triazol-4-ium bromide(RoO9-3846) as a white solid. To a mixture of 30 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluoro-phenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxybenzyl)-1H-[1,2,4]triazol-4-ium bromide, 10.9 g of Boc-(L)-proline and 2.8 g of N,N-dimethylaminopyridine in 1.2L of dichloromethane was added 17.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred for 1.5 h at room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2 /MeOH=14/1) to give 30.9 g(79%y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide as a white solid. 30.9 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide was stirred in 600 mL of 10% TFA-dichloromethane for 5 h at room temperature and the solvent was removed in vacuo. The residue was diluted with ether and the precipitate was washed with ether to give 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.[OH-].[CH2:15]([N+](CC)(CC)C1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC>[CH2:15]([O:12][C:11](=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC[N+](CC)(Cc1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(Cc1c[nH]c2ccccc12)OCc1ccccc1
Yield: 80.4 %

Procedure:
Indole 3-acetic acid 1 (9.45 g, 0.054 mol) was dissolved in methanolic benzyl diethyl anilinium hydroxide (0.54 mol) and the solvent removed in vacuo. The oily residue of the benzyl dimethyl anilinium salt was agitated with benzene, the benzene evaporated and the salt refluxed in toluene (170 ml, 1 h). Traces of unreacted acid and dimethyl aniline by-product were removed by extracting the toluene solution with water, dilute hydrochloric acid (1N) and water. The organic layer was dried over sodium sulphate and concentrated in vacuo to obtain the crude product. Final purification was obtained by crystallization in EtOAc:Hexane to give 11.52 g (80%) indole-3-acetic acid benzyl ester 13 as white crystals (melting point 71°-72° C.); IR (Nujol, cm-1); 3 400, 1, 720; 1H-NMR (CDCl3, δ): 3.8 (s, 2H), 5.1 (s, 2H) 6.8-8.0 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:30][CH3:31]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:13]([O:15][CH2:30][CH3:31])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2
Reactant: CCI
Reactant: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid (17 g, 46.6 mmol) in DMF (200 mL) was added Cs2CO3 (30.4 g, 93.2 mmol), followed with the addition of iodoethane (11 g, 69.9 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C19H24BrNO3: 394.1 (M+H+); Found: 394.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][C@@H:15]1[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][C@@H:15]2[CH3:24])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 2.12 g, 0.02 mol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.0 g, 0.02 mol) in dichloromethane (200 mL) was added HOBt (1.77 g, 0.02 mol) and N-methyl morpholine (3.8 mL, 0.03 mol) and then the mixture was stirred for 1 h at room temperature. EDC HCl (3.98 g, 0.0208 mol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was added to 2N hydrochloric acid (200 mL). The organic layer was washed with sodium bicarbonate (200 mL), water (250 mL), and brine. The organic layer was dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to get methyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 3.3 g (72%) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]1[C:19](=[O:40])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35](O)=[O:36])=[CH:29][C:28]2=[O:38])=[CH:23][C:22]=1[F:39])=[O:5])[CH3:2].Cl.[CH3:42][NH:43][CH3:44].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:7]([C:19](=[O:40])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35](=[O:36])[N:43]([CH3:44])[CH3:42])=[CH:29][C:28]3=[O:38])=[CH:23][C:22]=2[F:39])[CH:8]1[C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)O)cc2=O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)N(C)C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.8 %

Procedure:
A mixture of 23 mg (0.04 mmol) of (1SR,2RS,3SR) 2-[4-(4-carboxymethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl) cyclopropanecarboxylic acid ethyl ester (example 155), 5 mg (0.06 mmol) of dimethylamine hydrochloride, 1 mg of 1-hydroxybenzotriazole, and 25 ul (0.23 mmol) of N-methylmorpholine in 2.5 ml of DMF was treated with 11 mg (0.06 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at RT during 10 hrs. The mixture was poured into a 2M aqueous solution of HCl and extracted with AcOEt. Drying of the combined organic phases over Na2SO4, filtration, evaporation of the solvent and chromatography on silica gel with AcOEt/MeOH 10:1 gave 22 mg (95%) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[4-(4-dimethylcarbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester. Light brown solid. MS: 600 (M+H)+.
Reaction SMILES: [NH2-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([N:23]1[CH2:26][CH:25](OS(C)(=O)=O)[CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[O:9]([CH:25]1[CH2:26][N:23]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 8.6 g (0.22 mole) of sodium amide in 100 mL of dry toluene was added 18.8 g (0.2 mole) of phenol in 50 mL of dry toluene. The mixture was stirred at 60° C. for 2 hr. and the reaction temperature raised to 80° C. A solution of 63.4 g (0.2 mole) of 1-benzhydryl-3-methanesulfonyloxyazetidine (J. Org. Chem. 37, 3954 (1972)) in 200 ml of dry toluene was added dropwise. After stirring 2 hr at 80° C. the mixture was cooled and water added. The toluene was extracted with dilute NaOH solution, dried (Na2SO4) and concentrated. About one-third of the residue was removed. The rest of the residue was crystallized twice from water-isopropyl alcohol. Yield 9.3 g (15%); m.p. 83°-85° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.O>C1(C)C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: Clc1ccc(Br)cn1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 130 °C
Yield: 79.7 %

Procedure:
A mixture of piperazine (107 g, 1.24 mol) and 2-chloro-5-bromopyridine (30 g, 156 mmol) in toluene (150 mL) was heated at 130° C. for 2 hours, The reaction mixture was cooled to room temperature and toluene (400 mL) and water (200 mL) were added. The organic phase was isolated and the aqeuous phase was extracted once with toluene (100 mL). The collected organic phases were washed with water (150 mL) and brine (100 mL), dried over magnesium sulphate and evaporated to dryness in vacuo to give 30.1 g (80%) of 1-(5-bromopyridin-2-yl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13]OS(C)(=O)=O)=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(#N)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CN1CCN(CC#Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methanesulfonic acid 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynyl ester (150 mg), potassium carbonate (64 mg), N-methylpiperazine (45 μL) and acetonitrile (5 ml) were stirred at 50° C. for 3 hours. The reaction mixture was then cooled, diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvents reduced in vacuo to yield 2-chloro-6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (101 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2([CH:15]=[O:16])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2([C:15]([OH:24])=[O:16])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)=O
Reactant: Cc1cccc(C)c1COc1cccc(C2(C=O)CC2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(C2(C(=O)O)CC2)c1
Reaction time: 6 h

Procedure:
To a stirred solution of 1-(3-(2,6-Dimethylbenzyloxy)phenyl)cyclopropanecarbaldehyde (Step D, 3.5 g, 12.5 mmol) in acetone (50 ml) was added drop wise jones reagent (15 ml) at room temperature. The reaction mixture was stirred for 6 hours, diluted in EtOAc and washed with water, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:13]1[C@@H:17]2[CH2:18][CH2:19][C@@H:20]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[C@@H:16]2[CH2:15][NH:14]1.C1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:2]([F:12])([F:11])[F:1])[CH:10]=1)[CH2:6][N:14]1[CH2:15][C@H:16]2[C@H:20]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH2:19][CH2:18][C@H:17]2[CH2:13]1
Reactant: O=S(=O)(N[C@@H]1CC[C@H]2CNC[C@H]21)c1cccc(C(F)(F)F)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: O=S(=O)(N[C@@H]1CC[C@H]2CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]21)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by substituting 3,5-bis(trifluoromethyl)benzaldehyde for 3-(trifluoromethyl)benzaldehyde and N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)-3-(trifluoromethyl)benzenesulfonamide from Example 191 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.53 (d, J=7.4, 1H), 8.42 (s, 1H), 8.30 (d, J=7.9, 1H), 8.03 (s, 1H), 7.96 (s, 2H), 7.81 (d, J=7.8, 1H), 7.60 (t, J=7.9, 1H), 3.82-3.74 (m, 1H), 3.59 (s, 2H), 2.68-2.64 (m, 1H), 2.59-2.49 (m, 2H), 2.38-2.33 (m, 1H), 2.23 (dt, J=5.9, 8.9, 2H), 1.97-1.81 (m, 2H), 1.59 (ddd, J=8.2, 11.8, 13.0, 1H), 1.35-1.24 (m, 1H); MS (ESI+) m/z 561 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCN(c3ccc4c(cnn4C4CCCCO4)c3)CC2)cc1
Temperature: 75 °C
Yield: 54.7 %

Procedure:
To a solution of the 5-bromo-1-tetrahydro-2H-pyran-2-yl-1H-indazole (250 mg, 0.889 mmol) obtained in Reference Example 5 in toluene (12 ml) were added 1-benzylpiperazine (0.24 ml, 1.35 mmol) and sodium tert-butoxide (128 mg, 1.33 mmol) at room temperature. After deaeration, bis(tri-o-tolylphosphine)-palladium(II) dichloride (70 mg, 0.0891 mmol) was added thereto and the resulting mixture was stirred at 75° C. for three and a half hours. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate=5/2) to obtain 5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (183 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:11]=[C:10]1[C:4]2[S:3][C:2]([NH:1][C:19](=[O:20])[CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:22][CH3:23])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C(=O)Nc1nc2c(s1)C(=O)CCC2)c1ccccc1
Reaction time: 16 h

Procedure:
2-Amino-5,6-dihydro-4H-benzothiazol-7-one (34 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (31 mg, 0.099 mmol, 49%). ESI-MS m/z calc. 314.1. found 315.3 (M+1)+ Retention time 2.90 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[C:14]([NH2:16])=[O:15])[C:5]([Cl:17])=[CH:4][N:3]=1.[CH2:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1)[CH3:19].COCCO.Cl.O1CCOCC1>>[Cl:17][C:5]1[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[C:14]([NH2:16])=[O:15])=[N:7][C:2]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:18][CH3:19])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4C(N)=O)n3)cc2CC1
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
Into a microwave vial was added cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclopentane-carboxylic acid amide (80 mg, 0.0003 mol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (61 mg, 0.00032 mol) in 2-methoxyethanol (4 mL, 0.06 mol). To this reaction mixture was added 4N HCl-dioxane (0.04 g, 0.0003 mol) and the contents subjected to microwaves at 120° C. for 10 min. HPLC indicated no starting material remaining. A solid had precipitated out of the reaction mixture and was collected by filtration. The white solid was dried in vacuum at 50° C. overnight to give cis-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]-azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclopentanecarboxylic acid amide (30 mg, 20%). MP: 237-242° C.; 1HNMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.73 (s, 1H), 8.06 (s, 1H), 7.60 (s, 1H), 7.58 (d, 1H, J=), 7.46 (m, 1H), 7.16 (m, 2H), 4.43 (m, 1H), 3.62 (m, 5H), 3.18 (m, 2H), 2.87-2.98 (m, 4H), 1.59-1.75 (m, 5H), 1.59 (m, 1H), 1.27 (t, 3H, J=7.3 Hz); MS (m/e) 429 (M+1).