Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.O.[OH-].[Na+].Cl[C:12]1[C:17]([NH2:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1>CCO>[Cl:19][C:15]1[CH:14]=[N:13][C:12]2[S:1][CH2:2][C:3](=[O:5])[NH:18][C:17]=2[CH:16]=1
Reactant: CCOC(=O)CS
Reactant: Nc1cc(Cl)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CSc2ncc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of ethyl 2-mercaptoacetate (2.0 mL, 18.4 mmol) in water (5.03 mL, 12.27 mmol) was added NaOH (0.491 g, 12.27 mmol). The reaction was stirred at rt for 10 min. After this time a solution of 2,5-dichloropyridin-3-amine (2.0 g, 12.27 mmol) in EtOH (20 mL) was added and the reaction was heated at reflux for 4 days and cooled to rt. The resulting precipitate was filtered and washed with hexanes (50 mL) and MeOH (5 mL) to give 7-chloro-1H-pyrido-[2,3-b][1,4]thiazin-2(3H)-one as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (1H, d, J=0.6 Hz), 8.15 (1H, d, J=2.2 Hz), 7.31 (1H, d, J=2.3 Hz), 3.59-3.74 (2H, m). Mass Spectrum (ESI) m/e=201.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccn(CCCO)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 38 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (prepared in Example 83, 0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (56 mg, 57%) as a colorless oil: [α]30589=−20.0° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C21H26N3O2F3 (M+H)+ 410.2050, observed 410.2050; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.19 (m, 2H, CH2), 1.34-1.80 (m, 8H, 4×CH2), 1.79-1.91 (m, 2H, CH2), 2.03-2.21 (m, 1H, CH), 3.29-3.38 (m, 2H, OCH2), 3.84-3.93 (m, 1H, ArCH), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.55 (t, J=5.0 Hz, 1H, OH), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.55-7.74 (m, 4H, Ar), 10.74 (s, 1H, NH).
Reaction SMILES: [C:1]([CH:4]([S:28]([CH3:30])=[O:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH3:27])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[O:12])(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([CH:4]([S:28]([CH3:30])(=[O:39])=[O:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH3:27])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)=[O:12])(=[O:3])[NH2:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CC(C(N)=O)S(C)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CC(C(N)=O)S(C)(=O)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To 274 mg of 5-[2-carbamoyl-2-(methylsulfinyl)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 100 ml of methylene chloride and 155 mg of mCPBA, and the mixture was stirred for 3 hours. Saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the insolubles were filtered off. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=50:1 to 20:1) to obtain 201 mg of aimed product as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:17][C:16]=1[CH3:36])(=O)=O>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]#[C:21][C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)=[C:16]([CH3:36])[CH:17]=3)=[N:24][CH:25]=2)=[CH:34][CH:33]=1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1CCOS(C)(=O)=O
Reactant: CC1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1CCN1CCC(C)CC1
Temperature: 69 °C

Procedure:
0.09 mL (0.77 mmol) of 4-methylpiperidine was added to a solution of 110 mg (0.26 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenyl}ethyl methanesulfonate in 2 mL of DMF and heated to 69° C. After the reaction had ended, the reaction solution was cooled and the precipitate formed was suction filtered. Yield: 40 mg (36% of theoretical); C28H29ClN2 (M=428.996) C28H29ClN2; calc.: molpeak (M+H)+:429/431 (Cl); found: molpeak (M+H)+:429/431 (Cl); HPLC-MS: 5.96 minutes (method G).
Reaction SMILES: [C:1]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:1]([C:13]1[CH:14]=[C:15](/[CH:16]=[CH:26]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:19][CH:20]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC#Cc1cccc(C=O)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC#Cc1cccc(/C=C/C(=O)OCC)c1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of 3-(1-dodecynyl)benzaldehyde (23.0 g) in toluene (150 ml) was added carbethoxymethylenetriphenylphosphorane (35.5 g) in one portion. The mixture was warmed at 80° C. for 5 hr, allowed to cool to room temperature, and concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with ethyl acetate/hexane/1:15). The appropriate fractions were collected and evaporated to afford 21.1 g (73%) of product.
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:10]1([NH:13][CH:5]2[CH2:6][CH2:7][C:2]([CH3:9])([OH:1])[CH2:3][CH2:4]2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: CC1(O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(O)CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
4-Hydroxy-4-methylcyclohexanone (440 mg, 3.43 mmol) was dissolved in 1,2-dichloroethane (15 ml), followed by sequential addition of cyclopropylamine (0.26 ml, 3.78 mmol), NaBH(OAc)3 (1.16 g, 5.49 mmol), and acetic acid (0.20 ml, 3.43 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 20 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (15 ml×4). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 417 mg of yellow solid (72%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:31]([N:17]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCSC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCCCCCCCCCCCSC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from dodecyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-thiocarboximidate and benzoyl chloride, there is obtained dodecyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]-azepine-6-thiocarboximidate as a resin, mass spectrum m/e: M+ 526 (23), 357 (18), 194 (94), 105 (100);
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:11]1)=[O:5].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[C:20]1([CH:17]2[CH2:16][CH2:15][CH:14]([N:12]3[CH2:11][CH:10]([NH:9][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]4[CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:2]=4[N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:26])[CH2:13]3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: C1CCNC1
Product: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1N1CCCC1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from coupling of 2-fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide (as prepared in Example 66) and pyrrolidine (Aldrich) using the procedure described in Example 69.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[N:20]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:19]([CH3:33])([CH3:32])[CH2:18]3)[CH2:10][C:9]2([CH3:35])[CH3:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:37]1[O:42][CH2:41][C:40]2([CH2:47][O:46][P:45](Cl)[O:44][CH2:43]2)[CH2:39][O:38]1>>[CH:1]1([O:7][N:8]2[C:9]([CH3:35])([CH3:34])[CH2:10][CH:11]([N:16]([CH:17]3[CH2:18][C:19]([CH3:33])([CH3:32])[N:20]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:21]([CH3:23])([CH3:24])[CH2:22]3)[P:37]3[O:42][CH2:41][C:40]4([CH2:47][O:46][P:45]([N:16]([CH:17]5[CH2:22][C:21]([CH3:23])([CH3:24])[N:20]([O:25][CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]6)[C:19]([CH3:33])([CH3:32])[CH2:18]5)[CH:11]5[CH2:10][C:9]([CH3:35])([CH3:34])[N:8]([O:7][CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]6)[C:13]([CH3:15])([CH3:14])[CH2:12]5)[O:44][CH2:43]4)[CH2:39][O:38]3)[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)CC(NC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Product: CC1(C)CC(N(C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)P2OCC3(CO2)COP(N(C2CC(C)(C)N(OC4CCCCC4)C(C)(C)C2)C2CC(C)(C)N(OC4CCCCC4)C(C)(C)C2)OC3)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from bis(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)amine and 3,9-dichloro-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane according to the procedure of Example 14.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[CH3:15]
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccccn1
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccccn1
Yield: 34 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and pyridine-2 carbaldehyde in 34% yield as a colourless oil.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:27]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:1][CH2:2][OH:27])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: O=[O+][O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
A solution of (R)-6-allyl-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (334 mg, 0.80 mmol) in dry CH2Cl2 (20 mL) was treated with ozone at −78° C. until the reaction mixture became blue. Then the mixture was flushed with oxygen to remove excess ozone. To the above mixture was added NaBH4 (273 mg, 7 mmol) at 0° C. and the reaction mixture was stirred for 4 hrs at ambient temperature under nitrogen. The reaction mixture was washed with water and then extract with CH2Cl2 twice. The combined organic phases were dried over NaSO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (118 mg, 35%). 1H NMR (CD3OD): 1.50 (m, 3H), 2.12 (m, 2H), 2.29 (m, 2H), 2.50 (m, 1H), 3.10 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 4.56 (m, 1H), 5.50 (m, 1H), 6.86 (m, 2H), 7.10 (m, 2H), 7.30 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH3:11])[CH:9]=[C:8](I)[C:6]=2[N:7]=1.[CH3:13][S:14]([NH:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH3:11])[CH:9]=[C:8]([C:22]3[CH:23]=[C:18]([NH:17][S:14]([CH3:13])(=[O:15])=[O:16])[CH:19]=[CH:20][CH:21]=3)[C:6]=2[N:7]=1
Reactant: Cn1cc(I)c2nc(Cl)ncc21
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)c2nc(Cl)ncc21
Temperature: 100 °C
Yield: 68 %

Procedure:
To a solution of 2-chloro-7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (0.140 g, 0.48 mmol, 1.0 eq.) in DMF (6 ml) was added 3-methanesulfonylaminophenylboronic acid (0.124 g, 0.576 mmol, 1.2 eq.) followed by aqueous Na2CO3 (2M, 0.7 ml, 1.44 mmol, 3.0 eq.). A flow of nitrogen was bubbled through the mixture during 15 to 20 min before adding Pd[PPh3]4 (0.055 g, 0.048 mmol, 0.1 eq.). The mixture was then heated up to 100° C. overnight. After cooling down the reaction mixture to room temperature a large amount of water (around 60 ml) was added and the mixture extracted with ethyl acetate (3 times). After evaporation the residue was purified by column chromatography using petroleum spirit/ethyl acetate (1:4) as eluent. The product was obtained as a pale yellow solid (110 mg, 68%). LRMS (EI): m/z calcd for [M+H]+ 337.05 found 337.2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:12]2[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=3)[CH2:10][CH2:11]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (0.850 g, 3.4 mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in dichloromethane (10 mL) was stirred for 2 hours at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](=O)[CH2:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13]1>C(#N)C>[CH2:3]([N:10]1[C:22]([C:20]2[CH:19]=[CH:18][C:17]3[O:12][CH2:13][CH2:14][CH2:15][C:16]=3[CH:21]=2)=[CH:23][C:24]([C:25]([F:28])([F:26])[F:27])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNCc1ccccc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc2c(c1)CCCO2
Agent: Cl
Solvent: CC#N
Product: FC(F)(F)c1cc(-c2ccc3c(c2)CCCO3)n(Cc2ccccc2)n1
Yield: 39.7 %

Procedure:
A solution of benzylhydrazine dihydrochloride (394 mg, 2.03 mmol) and 1-(3,4-dihydro-2H-1-benzopyran-6-yl)-4,4,4-trifluorobutane-1,3-dione (49b) (500 mg, 1.84 mmol) in acetonitrile (80 mL) was refluxed for 16 hours. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate (5 mL). The organic layer was successively washed with water (10 mL) and brine (10 mL) before being dried over sodium sulfate and concentrated in vacuo. The oil was purified by preparative TLC (cyclohexane/ethyl acetate 100/0 to 90/10) to provide the desired pyrazole (49c) (260 mg, 0.73 mmol, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:32]=[CH:33][C:34]([CH3:38])=[C:35]([OH:37])[CH:36]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][CH2:47][O:48][CH3:49]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:32]=[CH:33][C:34]([CH3:38])=[C:35]([O:37][CH2:46][CH2:47][O:48][CH3:49])[CH:36]=5)=[N:23][N:22]=4)=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COCCBr
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(C)c(O)c5)c5ccccc45)cc3)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)ccc1C
Reaction time: 0.08 h

Procedure:
5-(4-(4-(7-Methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)-2-methylphenol (120 mg, 239 μmol) and cesium carbonate (234 mg, 718 μmol) were combined in DMF and stirred for 5 min. 1-Bromo-2-methoxyethane (66.5 mg, 479 μmol) was added and the mixture was stirred for 1 h. The mixture was then filtered and purified using reverse phase chromatography to provide the titled product. MS: M+H+=560.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([Br:22])=[CH:20][CH:21]=2)O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].O=S(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([Br:22])=[CH:20][CH:21]=2)[Cl:26])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Br)nc1)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)Oc1ccc(C(Cl)c2ccc(Br)nc2)cc1OC(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution [3,4-Bis(difluoromethoxy)phenyl]-(6-bromo-3-pyridyl)methanol (15.8 g,40.0 mmol) in 400 mL of CH2Cl2, was added 3.8 mL (52.0 mmol) of SOCl2. The solution was stirred 45 minutes at room temperature and poured into a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dry over MgSO4 and concentrated under reduced pressure. The crude chloride was used directly for the next step without any purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:32]([CH2:31][N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)#[N:33]
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(CC#N)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (39 mg, 0.10 mmol), 2-bromoacetonitrile (8 uL, 0.12 mmol) and Potassium Carbonate (28 mg, 0.20 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4 and concentrated. The crude product was purified by reverse phase HPLC to give N-(5-(4-(cyanomethyl)piperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 175. MS m/z 427.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.37(d, 1H), 7.94(s, 1H), 7.87(d, 1H), 7.68(d, 2H), 7.55(s, 1H), 7.48-7.44(m, 3H), 7.36(dd, 1H), 3.74(s, 2H), 3.67(s, 2H), 3.17(t, 4H), 2.69(t, 4H), 2.54(s, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(F)c3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 4-fluoro-naphthalene-1-carboxylic acid (232 mg, 1.22 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (250 mg, 1.22 mmol), HATU (696 mg, 1.83 mmol) in anhydrous DMF (8 mL) is added DIPEA (302 μL, 1.83 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (43) as white solid (340 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](OC(=O)C(C)(C)C)[N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1cccc(Cl)c1
Yield: 32 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) (From Example 28) was coupled with 3-chloro-benzoyl chloride (0.4 mmol) and triethylamine in DCM at 0° C. to give 41 mg of the titled compound as a white solid.