Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH:13]([CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:12][C@@H:13]([CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(C)CCCCCO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC[C@H](C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of p-toluenesulfonyl chloride (19.9 g, 0.1 mol) dissolved in toluene (30 ml) was dropwise added with stirring under ice cooling, to a solution of 6-methyloctanol (15.4 g, 0.1 mol) prepared according to the method of a literature (M.C.L.C. 27,417 (1974)) and dissolved in dry pyridine (43 ml), followed by slowly returning the temperature to room temperature, allowing the resulting material to stand overnight, extracting the reaction mixture with toluene after completion of the reaction, washing the resulting organic layer with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, drying the layer, and distilling off toluene to obtain oily (S)-6-methyloctyl-p-toluenesulfonate (26.1 g).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:18]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[O:25])=[CH:20][CH:21]=1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1Nc2cccnc2N(C(=O)c2ccncc2)c2ccccc21

Procedure:
A mixture of 40.4 gm (0.191 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 46.0 gm (0.258 mol) of isonicotinic acid chloride hydrochloride, 42 ml (0.52 mol) of pyridine, and 600 ml of anhydrous dioxane was refluxed for three hours. After cooling, the mixture was filtered, the filter residue was taken up in 300 ml of water, and the solution obtained was extracted twice, each time with 100 ml of dichloromethane. The aqueous phase was made alkaline with sodium hydroxide solution and exhaustively extracted with methylene chloride. The methylene chloride extracts thus obtained were washed with water and dried over sodium sulphate, and the solvent was eliminated in vacuo. The residue was recrystallized from hot methanol. After washing with ether, the resulting beige-colored crystals melted at 265°-266° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8]([O:10]CC)=O.O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:10])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[N:4][C:3]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NN
Reactant: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nc(-n2cncn2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 15 ml of ethanol was dissolved 0.215 g of 3-amino-4,5-diethoxycarbonyl-2-phenyl-6-(1,2,4-triazol-1-yl)pyridine, whereto 1 ml of hydrazine monohydrate was added. The mixture was heated under reflux for 7 hours. After cooling, the resulting yellow crystals were collected by filtration and washed with ethanol. The crystals were suspended in 20 ml of water and the suspension was acidified by addition of 1 ml of acetic acid. Thereafter, the crystals were collected by filtration, washed with water and dried to give 0.11 g of the title compound.
Reaction SMILES: C1([SeH-](C2C=CC=CC=2)=[Se])C=CC=CC=1.[BH4-].[Na+].[O:17]1[C@H:19]2[C@:20]3([CH2:36][CH2:35][C@H:34]4[C@@H:25]([CH2:26][CH2:27][C:28]5[CH:29]=[C:30]([O:37][CH3:38])[CH:31]=[CH:32][C:33]=54)[C@@H:23]3[CH2:24][C@@H:18]12)[CH2:21][CH3:22].OO>C(O)C>[CH3:38][O:37][C:30]1[CH:31]=[CH:32][C:33]2[C@@H:34]3[C@H:25]([C@H:23]4[C@@:20]([CH2:36][CH2:35]3)([CH2:21][CH3:22])[C@H:19]([OH:17])[CH:18]=[CH:24]4)[CH2:26][CH2:27][C:28]=2[CH:29]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C[C@H]1O[C@H]12
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C=C[C@H]2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.7 g. of diphenyldiselenide is dissolved in 200 ml. of absolute ethanol and combined at room temperature with 1.0 g. of sodium borohydride. After the yellow solution has lost its color, 5.0 g. of 16α,17α-epoxy-3-methoxy-18 -methyl-1,3,5(10)-estratriene is added thereto and the mixture is heated under reflux for 30 hours. The solution is then cooled to 0° C. Dropwise, 11ml. of 30% H2O2 is added to the reaction solution and the latter is then gradually heated to 50° C. After 2 hours, the solution is introduced into ice water. The precipitate is vacuum-filtered, washed with water, and taken up in methylene chloride. After chromatography on silica gel with 6-8% acetone/hexane, 1.9 g. of 3-methoxy-18-methyl-1,3,5(10),15-estratetraen-17α-ol is obtained as an oily product. [α]D 20 = -108°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].[Cl-].[Na+]>C(O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:15]([C:14]#[N:18])[C:16]#[N:17])=[CH:6][CH:5]=1
Reactant: N#CCC#N
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
First, 10.0 g of 4-(trifluoromethoxy)benzaldehyde and 3.50 g of malononitrile were dissolved in 60 ml of 70% (w/w) aqueous ethanol, to which a catalytic amount of benzyltrimethylammonium hydroxide was added, and the mixture was stirred at room temperature overnight. Then, a saturated aqueous sodium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from t-butyl methyl ether and hexane to give 9.24 g of (4-(trifluoromethoxy)benzylidene)malononitrile.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:31][CH3:32])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:7]2.[BH4-].[Na+].O>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([OH:15])[CH:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:31][CH3:32])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:7]2
Reactant: CCN(CCCCCC1Cc2cc(OC)c(OC)cc2C1=O)Cc1ccccc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCCCCC1Cc2cc(OC)c(OC)cc2C1O)Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
To a solution of the 5,6-dimethoxy-2-[5-[N-ethyl-N-[(2-methoxyphenyl)methyl]amino]pentyl]-1-indanone hydrochloride (0.75 g) in methanol (10 ml) was gradually added sodium borohydride (0.3 g) and the mixture was stirred at room temperature for 6 hours. The excess sodium borohydride was then decomposed by addition of water and the solvent was distilled off under reduced pressure. The product was extracted into dichloromethane and washed with water. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was distilled off to give 0.63 g of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]#[C:26][Si](C)(C)C)[CH:22]=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[F-].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[C:21]([C:31]([F:33])([F:34])[F:32])[CH:22]=[C:23]([C:25]#[CH:26])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C#C[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cc(C(F)(F)F)cc(S(=O)(=O)NC2CCCc3c2cnn3CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of [4-(3-trifluoromethyl-5-trimethylsilanylethynyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (40.0 mg, 0.076 mmol) in N,N-dimethylformamide and water (3 mL, 150:1) was added potassium fluoride (23.0 mg, 0.30 mmol). The mixture was stirred at room temperature for 4 hours. The resulting mixture was poured into ice and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-ethynyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (34.0 mg, 98.2%) as a white solid. MS calcd. for C20H20F3N3O4S 455, obsd. (ESI+) [(M+H)+] 456.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:8]([C:9](O)=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([CH3:15])=[N:5]1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:8]([C:9]([Cl:19])=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([CH3:15])=[N:5]1
Reactant: Cc1nn(CC(F)(F)F)c(C(=O)O)c1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1nn(CC(F)(F)F)c(C(=O)Cl)c1[N+](=O)[O-]

Procedure:
The above acid (22 g, 0.11 mol) is added in portions at 70°-90° C. to a stirred acid mixture prepared by adding 30 ml conc. sulfuric acid to 15 ml of 90% nitric acid. After stirring two hours at 95°, the mixture is poured into 75 g of ice. The collected precipitate is dried to give 23 g, 1-(2,2,2-trifluoroethyl)-3-methyl-4-nitropyrazole-5-carboxylic acid, mp 135°-138° C. This nitro acid (23 g, 0.09 mol) is mixed with 21 g (0.1 mol) of phosphorus pentachloride and heated on a steam bath for 2.5 hr, filtered, and evaporated in vacuo to give 20 g of 1-(2,2,2-trifluoroethyl-3-methyl-4-nitropyrazole-5-carbonyl chloride as an oil. The acid chloride (20 g) in 30 ml of acetone is added dropwise to 130 ml cold concentrated ammonium hydroxide and the mixture is filtered after stirring one hour to give 16 g of 3-methyl-4-nitro-1-(2,2,2-trifluoroethyl)-5-pyrazolecarboxamide, mp 205°-207° C. from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[Cl-].[NH4+]>CN1CCCC1=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2ccn(Cc3ccccn3)c2c1
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
—Sodium hydride (60% dispersion in oil, 15.5 g, 319 mmol) was added in portions to a solution of 6-nitroindole (23.5 g, 145 mmol) in 1-methyl-2-pyrrolidinone (1000 ml). After 45 min. stirring, 2-chloromethyl-pyridine hydrochloride (28.2 g, 174 mmol) was added in portions. Stirring was continued for 1 h and the reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 1:1→ethyl acetate) afforded 6-nitro-1-pyridin-2-ylmethyl-1H-indole (30 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][NH:23][C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCCC(C)C>ClCCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: Fc1ccc(-c2nc3c(nc2-c2ccc(F)cc2F)NCCC3)c(F)c1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(F)cc3F)c(-c3ccc(F)cc3F)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture comprising 2,3-bis(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate CC) (310 mg, 0.863 mmol) in 1,2-dichloroethane (10 ml) was added to ethyl 7-oxoheptanoate (446 mg, 2.59 mmol) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (914 mg, 4.31 mmol) was added and stirring continued at RT for 3 days. The mixture was heated to 60° C. for 3 h and allowed to cool to RT. The resulting mixture was applied to a pre-wet (iso-hexane) Isolute® cartridge (silica) and eluted with 20-33% EtOAc in iso-hexane to afford the titled compound;
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)[CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=3)[N:24]([CH2:32][C:33]([OH:35])=[O:34])[C:23]=2[CH3:36])(=O)=[O:20])=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=3)[N:24]([CH2:32][C:33]([O:35][CH2:1][CH3:2])=[O:34])[C:23]=2[CH3:36])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc2c(c1)c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(S(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Reaction time: 1 h

Procedure:
MCPBA (1.07 g) was added to a solution of example 1 part a) (1.79 g) in dichloromethane (20 ml) at 0° C. The reaction mixture was stirred for 1 h, after which further mCPBA (53 mg) was added and stirred for a further 30 min. The reaction mixture was allowed to reach room temperature and the sub-title compound was obtained as a white solid after filtration (0.68 g). Used directly in the next step without further purification.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[C:13]1([CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:24][C:23]1[C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:20]([CH3:21])[N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[N:3]=1
Reactant: CC(=O)C(C(C)=O)c1ccccc1
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 3-phenylpentane-2,4-dione: MS (ESI) m/z 293 [M+H]+, 1H-NMR (CDCl3) δ 7.45-7.27 (9H, m), 3.79 (2H, t, J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.26 (3H, s).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:25]4[C:24]5[C@@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21][C:20]=5[S:19][C:18]=4[N:17]=[CH:16][N:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)(O)[O-].[Na+]>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([O:13][C:14]3[C:25]4[C:24]5[C@@H:23]([CH2:26][CH:27]=[O:28])[CH2:22][CH2:21][C:20]=5[S:19][C:18]=4[N:17]=[CH:16][N:15]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
For the preparation of the starting material compound 29.2, please see Example 29. A solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (190 mg, 0.47 mmol, 1.00 equiv) in 10 mL of dichloromethane was added Dess-Martin periodinane at 0° C. in a water/ice bath under nitrogen. The resulting mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was then diluted with saturated aqueous sodium bicarbonate and extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:1) to afford 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetaldehyde (130 mg, 69%) as a colorless oil. MS (ES): m/z 402 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23].C(N(CC)CC)C>CN(C=O)C.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>[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[C:23][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=NC2(N=C1N)c1cc(C#CC(C)(C)C)ccc1CC21CCC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
To a solution of 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54, 0.100 g, 0.31 mmol) in DMF (10 mL) under argon was added 3,3-dimethyl-but-1-yne (0.039 g, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) and triethylamine (1.31 mL, 9.43 mmol). The reaction mixture was stirred at r.t. for 5 min before addition of cuprous iodide (8.98 mg, 0.05 mmol). The reaction mixture was stirred overnight at 65° C. and then partitioned between sat aq. NaHCO3 and EtOAc. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by preparative chromatography to afford the title compound (0.039 g, 38% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.24 (s, 9 H), 1.47-1.66 (m, 4 H), 1.73-1.84 (m, 1 H), 2.09-2.17 (m, 1 H), 2.18 (s, 3 H), 3.16 (d, 2 H), 6.53 (d, 1 H), 6.60 (s, 2 H), 7.14 (dd, 1 H), 7.24 (d, 1 H); MS (ES+) m/z 320 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:8][CH2:7]1)C.O[Li].O>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[C:12]([CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:24])=[O:3])[CH2:11][CH2:10]1)=[O:23]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)c(OC)c2)CC1
Agent: [Li]O
Solvent: O
Product: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
To a solution of [4-(3,4-dimethoxy-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (0.45 g, 1.34 mmol in 6 mL of THF and 2 mL of methanol) was added LiOH.H2O (0.28 g, 6.7 mmol in 3 mL of water) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1 N HCl (pH 4), frozen at −78° C. and lyophilized for 24 hours to yield the title compound (0.40 g, 1.24 mmol). MS (ESI) m/z 308.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.16 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH2:9][C:8]2[N:7]([C:11]3[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=3)[N:6]=[CH:5][C:4]=2[CH2:3]1.[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][CH:2]2[CH2:10][CH2:9][C:8]3[N:7]([C:11]4[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=4)[N:6]=[CH:5][C:4]=3[CH2:3]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCOC(=O)c1sc(-n2ncc3c2CCC(N)C3)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(-n2ncc3c2CCC(NC(=O)c2nc(Cl)c(CC)[nH]2)C3)nc1C
Yield: 89.1 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(5-amino-4,5,6,7-tetrahydro-1H-indazol-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (242d) (50 mg, 0.16 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (28 mg, 0.16 mmol), WSC hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (22 mg, 0.16 mmol) and N-methylmorpholine (0.04 mL, 0.33 mmol), to obtain 66 mg of the title compound as a white solid (88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:41][CH3:42])=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C.ClC(OC(C)C)=O>ClCCl.O>[CH:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:38])([F:39])[F:40])[CH:28]=2)[C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:18][N:19]=2)[CH2:10][C@H:9]1[CH2:41][CH3:42])=[O:7])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC(C)C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
To a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.200 mmol; 120 mg) in dichloromethane (2.0 mL) is added trifluoroacetic acid (0.7 mL). The mixture is stirred for 1 hour, and then concentrated under reduced pressure. To a mixture of the obtained residue and N,N-diisopropylethylamine (1.6 mmol; 207 mg) is added isopropyl chloroformate (0.4 mmol; 49 mg). The mixture is stirred for 1 hour at room temperature, and then diluted with water and dichloromethane. The organic layer is separated to concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (51 mg, 73%); ESI-MS m/z: 599 [M+1]+, Retention time 2.15 min (condition A).