Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N:24]1([NH2:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[N:24]1([NH:30][C:15]([C:12]2[CH:13]=[N:14][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][CH:11]=2)=[O:17])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1cnc(C(=O)c2ccccc2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCOCC1)c1cnc(C(=O)c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
2-Benzoyl-pyrimidine-5-carboxylic acid (50 mg, 0.22 mmol) is dissolved in anhydrous DCM (5 mL), and a 2 M oxalyl chloride (0.26 mmol, 0.13 mL) solution in DCM is added at rt followed by one drop of DMF. The mixture is stirred at rt for 2 h, and then concentrated in vacuo. The residue is dissolved in DCM (5 mL), and morpholine-4-ylamine (0.24 mmol, 25 mg) is added, followed by DIPEA (0.44 mmol, 57 mg). The reaction mixture is stirred at rt overnight, and then concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 10% MeOH in DCM to afford 2-benzoyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide (42 mg) as a solid. MS: 313 (M+H). IC50=342 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-:27].[Na+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH2:25])=[O:27])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc2c(OCc3nnc4ccc(C#N)cn34)ccnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc2c(OCc3nnc4ccc(C(N)=O)cn34)ccnc2c1
Temperature: 50 °C
Yield: 95 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.5 mL). The reaction mixture was heated at 50° C. for 30 minutes. The reaction mixture was slowly poured in to cold saturated aqueous sodium bicarbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was transferred with dichloromethane/methanol to a flask and dried under high vacuum to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.050 g, 95% yield) as a tan solid. MS (ESI pos. ion) m/z: 350.2 (MH+).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.07 g oxazolo[4,5-b]pyridin-2(3H)-one dissolved in 85 ml of DMF under nitrogen is added 7.46 g NBS in 50 ml of DMF. This is allowed to stir at room temperature overnight. To this is added 35 ml of water and chilled. The solid material which separates is filtered and washed with 3×100 ml H2O. This is then dried in a vac oven at 70° C. and then used directly in the next step.
Reaction SMILES: CC1C=CC([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=CC=1.C(Cl)(=O)C(Cl)=O.C[N:29](C)C=O>ClCCl>[O:17]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:21][C:12]=2[CH:13]=[C:14]([C:18]([NH2:29])=[O:19])[CH2:15][CH2:16]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)C1=Cc2ccccc2OCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15g) in dichloromethane (6ml) were added oxalyl chloride (0.14ml) and dimethylformamide (catalytic amount) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was dropwise added to a solution of 4-((N-(3,5-dimethylcyclohexyl)-N-methyl)-aminomethyl)aniline (0.13g) and triethylamine (0.23ml) in tetrahydrofuran (10ml), under ice-cooling. Under nitrogen atmosphere, the mixture was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from diethyl ether-hexane to give N-(4-((N-methyl-N-(3,5-dimethylcyclohexyl))aminomethyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 133) (0.22g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=O)[CH:30]=[CH:31][CH:32]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>N1C=CC=CC=1>[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]3[NH:8][C:34]([CH2:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([Br:26])[CH:28]=4)=[N:9][C:5]=3[CH:4]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1cc(Cl)c(I)cc1N
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(Cc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a microwave vial containing a solution of Intermediate 11-1 (which was prepared from 5-chloro-4-iodo-1,2-phenylenediamine (Intermediate 1-6 of Example 1) and 4-biphenylboronic acid following the procedures of Step 9 in Example 1) (500 mg, 1.7 mmol) in pyridine 8 mL was added 3-bromo-phenyl acetic acid (365 mg, 1.7 mmol), followed by triphenyl phosphite (0.58 mL, 2.2 mmol). The reaction was run in a microwave reactor at 220° C. for 10 min. The solvent was partially removed in vacuo, then diluted with EtOAc (75 mL) and washed three times with 50 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo, and then purified by chromatography over silica (eluting with EtOAc/Hexanes=1/1) to give the title compound 14-1 as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([OH:15])[CH:17]=[CH2:18])=[C:4]([F:16])[CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Solvent: C1CCOC1
Product: C=CC(O)c1cnccc1-c1ccc(Cl)cc1F
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (0.5 g, 2.122 mmol) (prepared as in Example 5, Part B) in THF (25 mL) at −70° C. was added vinylmagnesium bromide (1.0 M in THF) (6.37 mL, 6.64 mmol) dropwise and the solution was stirred at this temperature for 45 min. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was used without purification in the next step. LCMS (ESI) m/e 264 [(M+H)+, calcd for C14H12ClFNO 264.0]; LC/MS retention time (Method C): tR=1.59 min.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[C:31]([O:35][C:36]([NH:38][C@@H:39]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:16][CH3:17])[CH2:11][N:10]([C:40](=[O:41])[C@@H:39]([NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To an iced slurry of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-2-carboxylate, TFA (174 mg, 0.394 mmol), (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (100 mg, 0.434 mmol), and HATU (225 mg, 0.591 mmol) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.207 mL, 1.182 mmol). The formed colorless slurry was stirred at room temperature overnight. Diluted with DCM, quenched with 5% citric acid. The organic layer was washed with 0.1 M NaOH and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with 5˜35% etOAc-hexane to yield the desired product (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylate (178 mg, 0.296 mmol, 75% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 1.12 (s, 9H), 1.46 (s, 9H), 1.86 (s, 3H), 2.60 (dd, J=12.97, 6.87 Hz, 1H), 2.90 (dd, J=12.82, 7.93 Hz, 1H), 3.74 (s, 3H), 4.11 (d, J=11.29 Hz, 1H), 4.35-4.48 (m, 2H), 4.73 (d, J=10.99 Hz, 1H), 7.36 (t, J=7.02 Hz, 1H), 7.42-7.51 (m, 3H), 7.54-7.71 (m, 5H). LC-MS (retention time: 3.34 min, method B), MS m/z 541 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:8]1([C:7]2[C:6]([CH2:5][C:4]([OH:3])=[O:23])=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:33]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccccc2Cl)c1-c1ccccc1
Yield: 36.9 %

Procedure:
8.0 grams 3,3-dibenzoyl-propionic acid-ethyl ester, 5.5 grams o-chlorophenylhydrazine hydrochloride, 2.5 grams sodium acetate and 4.0 grams glacial acetic acid were reacted and the reaction product recovered by a procedure analogous to the method set out in Example 21. 3.7 grams 3,5-diphenyl-1-(o-chlorophenyl)-pyrazol-4-acetic acid, melting at 191°-193° C., were obtained, representing a yield of 37%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH2:9][CH2:2][CH2:43][CH3:44])[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 29.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(pentyl)amine (101 mg, 1.0 mmol) for N-methylethanamine to afford 19.0 mg of the title compound (29.5%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].C([Li])CCC.[C:15]1(=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.Cl>O1CCCC1>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)([CH3:3])[CH3:2])=[CH:16]1
Reactant: CC(C)c1ccccn1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C1=CCc2ccccc21)c1ccccn1

Procedure:
A solution of 10.8 g (0.09 mol) of 2-isopropylpyridine in 47 ml of tetrahydrofuran was cooled to −20° C. and 62.5 ml of n-butyllithium (1.6M in hexane, 0.11 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature and was stirred for a further one hour. A solution of 15.84 g (0.12 mol) of 1-indanone in 12 ml of tetrahydrofuran was then added at such a rate that the temperature remained at 25° C. The mixture was stirred for a further 12 hours and hydrolyzed with 200 ml of dilute hydrochloric acid. The organic phase was separated off, the aqueous phase was extracted once with diethyl ether, the aqueous phase was subsequently neutralized with aqueous ammonia solution and was extracted three times with 100 ml each time of chloroform. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. This gave 16.6 g (77%) of 2-[1-(1H-inden-3-yl)-1-methylethyl]pyridine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:17]2[CH2:18][CH:19]([CH3:21])[CH2:20][CH:15]([CH3:14])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: CC1CNCC(C)C1
Solvent: CCO
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.51 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) was added therein, and the mixture was stirred for 8 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.40 g of 4-(2-butynyloxy)-5-fluoro-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (4)). Compound (4) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.3/1.
Reaction SMILES: C(S[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([F:34])[CH:20]=1)[C:14](=[O:35])[CH:13]=[CH:12]2)C1C=CC=CC=1.C(Cl)Cl.C(O)(=O)C.[S:43]([Cl:47])(Cl)(=[O:45])=[O:44]>O>[F:34][C:21]1[CH:20]=[C:19]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([S:43]([Cl:47])(=[O:45])=[O:44])=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:14]2=[O:35])[C:24]([O:25][CH3:26])=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Cl)ccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
A RBF cooled to 0° C., was charged with 6-(benzylthio)-1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (0.168 g, 0.346 mmol), DCM (3.30 ml), Acetic Acid (0.082 ml), and Water (0.082 ml). After stirring for 5 minutes at 0° C., sulfuryl chloride (0.028 ml, 0.346 mmol) was added and stirring was continued for an additional 1 hour at 0° C. The reaction was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.135 g, 0.292 mmol, 84% yield). m/z (ESI) 462.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[ClH:1].[CH:20]1([NH:26][C:2]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:4]([C:5]([NH:7][C:8]3[NH:12][N:11]=[N:10][N:9]=3)=[O:6])[CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Reactant: NC1CCCCC1
Solvent: O
Product: Cl
Product: O=C(Nc1nnn[nH]1)c1cc(NC2CCCCC2)c2ccccc2n1

Procedure:
4-Chloro-N(1H-tetrazol-5-yl)quinaldamide (0.55 g), cyclohexylamine (3 ml) and water (5 ml) were heated on a steam bath for 3 hours and cooled. The solid was collected and dried, m.p. 245° (d).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:11]3C=CC(F)=[C:15]([CH:18]=3)C#N)[C:3]=12.[CH3:23][C:24]([O-:27])(C)[CH3:25].[K+].[CH3:29][N:30](C=O)C>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:11]3[CH:18]=[CH:15][C:25]([C:29]#[N:30])=[C:24]([OH:27])[CH:23]=3)[C:3]=12
Reactant: CC(C)n1nc(-c2ccc(F)c(C#N)c2)c2c(N)ncnc21
Reactant: CN(C)C=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)n1nc(-c2ccc(C#N)c(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorobenzonitrile (BA151, 20 mg, 0.07 mmol) was dissolved in DMF (1 ml). t-BuOK (24 mg, 0.21 mmol) was added and the reaction was stirred at room temperature overnight. Reaction was then heated to 150° C. for 24 hours. The reaction was then concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA157—2 (7 mg), ESI-MS (M+H)+ m/z calcd 295.1, found 295.4 and BA157—3 (8 mg), ESI-MS (M+H)+ m/z calcd 310.1, found 310.4.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:9][CH:10]=1)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:4](=[O:21])[CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
54.1 Using general method A, with THF instead of DMF as solvent, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid ethyl ester (example 1.1) was coupled with tert-butyl-1-piperazine carboxylate to give 4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester. White solid. MS 465.1 ([M+H]+)
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][S:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH2:23]>C(O)(C)C.CC(C)=O>[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH:23][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][S:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(Cl)ncnc2cc1OCCSC
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCSC
Yield: 53.2 %

Procedure:
1M Ethereal hydrogen chloride (3.1 ml, 3.1 mmol) was added to 4-chloro-6-methoxy-7-(2-methylthioethoxy)quinazoline (0.8 g, 2.8 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (0.44 g, 3.12 mmol), (prepared as described for the starting material in Example 8), in isopropanol (25 ml). The mixture was heated at reflux for 2 hours, then allowed to cool. The resulting suspension was diluted with acetone and the precipitate collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/ammonia (100/8/1) to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthioethoxy)quinazoline (580 mg, 52%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:25][C:26]1([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:29][NH:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:28]3[CH2:29][C:26]([CH2:30][N:31]([CH3:33])[CH3:32])([F:25])[CH2:27]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C)CC1(F)CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 1.8 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g, 1.0 eq.) was dissolved in DCM (10 mL). The reaction mixture was cooled to −60° C., at which temperature 1-(3-fluoroazetidin-3-yl)-N,N-dimethylmethanamine (0.22 g, 1.2 eq) and T3P (50% in EtOAc) (1.08 g, 1.2 eq.) were added, followed by DIPEA (0.36 g, 2 eq.). The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography to give 12 mg of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino)methyl)-3-fluoroazetidin-1-yl)prop-2-en-1-one (3% yield). 1H NMR (400 MHz, CDCl3) δ=9.75 (s, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.24-7.21 (d, J=10.8 Hz, 1H), 5.69-5.66 (d, J=10.8 Hz, 1H), 4.37-4.25 (m, 2H), 4.22-4.15 (m, 2H), 2.82-2.76 (d, 2H), 2.35 (s, 2.35, 1H); LCMS for C19H19F7N5O [M+H]+ 466.4 found 466.3 at retention time 2.263 min