Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1>C(O)C>[CH3:1][NH:2][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc2ccccc2nc1Cl
Solvent: CCO
Product: CNc1nc2ccccc2cc1[N+](=O)[O-]
Yield: 91 %

Procedure:
Gaseous methylamine was bubbled through a suspension of 2-chloro-3-nitroquinoline (1.06 g, 5.1 mmol) in ethanol (20 ml) at 0° C. for 15 minutes. The solvent was removed under reduced pressure and the bright red residue was dissolved in dichloromethane (100 ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 2-methylamino-3-nitroquinoline (940 mg, 91%) as a red solid, m.p. 160° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.Cl.[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@H:29]1[CH3:34].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:25][CH:23]([F:24])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][O:33][C@@H:28]([CH3:27])[C@H:29]3[CH3:34])[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: C[C@@H]1NCCO[C@@H]1C
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1OCCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine, 8.41 g (50 mmol) of 2-difluoromethyl-benzimidazole and 55.3 g (400 mmol) of anhydrous potassium carbonate added to DMF (250 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and the resulting precipitates were washed with DMF and ethanol to obtain 15.7 g (yield: 86%) of 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine. (2) 0.36 g (0.98 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.38 g (yield: 87%) of the titled compound as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.O=S(Cl)Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][C:25]=1[Cl:31].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(Cl)Cl.O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:18][CH2:17][C:5]2[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])=[N:7][O:8][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[CH:26][C:25]=1[Cl:31]
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (13 g, 45.8 mmol) in CH2Cl2 (DCM) (200 mL) was added dropwise SOCl2 (40 mL, 336 mmol). The resulting mixture was stirred at rt for 2 h and the solvents were removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (DMF) (200 ml) and 4-bromo-3-chlorophenol (9.7 g, 47 mmol), K2CO3 (40 g, 290 mmol) and NaI (12 g, 80 mmol) were added to this solution. The mixture was stirred at 60° C. overnight, then cooled to rt, diluted with water (1000 mL) and extracted with ethyl acetate (EA) (500 mL×3). The combined organic phases were washed with brine (500 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CC) to give the title compound 1a (19 g, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
A solution of 2-fluorobenzoyl chloride (5.82 g, 0.0367 mol) and 4-bromoaniline (6.31 g, 0.0367 mol) in anhydrous dichloromethane (150 mL) was cooled to 0° C. and N,N-diisopropylethylamine (5.21 g, 0.0407 mol) was added under nitrogen atmosphere dropwise. The resulting mixture was stirred at ambient temperature for 24 hours, concentrated and the residue partitioned between ethyl acetate (120 mL) and water (100 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold diethyl ether (50 mL) and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluorobenzamide (9.6 g, 0.0326 mol) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:18][CH2:17][C:16]#[N:19])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CCN(Cc2ccccc2)CC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNCC1CCN(Cc2ccccc2)CC1
Yield: 102.2 %

Procedure:
A mixture of 1-(phenylmethyl)-4-piperidinemethanamine (0.076 mol) and acrylonitrile (0.076 mol) in ethanol (250 ml) was stirred and refluxed for 4 hours. The solvent was evaporated, yielding 20.0 g (102.4%, crude residue, used in next reaction step, without further purification) of 3-[[[1-(phenylmethyl)-4-piperidinyl]methyl]amino]-propanenitrile (interm. 14).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)([F:7])[F:6])C.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([F:6])([F:7])[C:4]([OH:15])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)C(F)(F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the above-described scheme, 2-(4-bromophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2f; 279.1 mg, 1.0 mmol), 1N K2CO3 solution (3.0 mL) and DMF (3.0 mL) were put into an eggplant flask, and the mixture was stirred at 25° C. for 18 hours. After the reaction, the reaction mixture was neutralized with 5% HCl solution, extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-bromophenyl)-2,2-difluoroacetic acid (Compound 4f) was obtained with a yield of 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:45][C:46]1[CH:47]=[C:48]([CH:57]=[CH:58][CH:59]=1)[CH2:49][N:50]1[CH:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51]1>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:56][CH2:55][C:52]2[CH:53]=[CH:54][N:50]([CH2:49][C:48]3[CH:57]=[CH:58][CH:59]=[C:46]([F:45])[CH:47]=3)[CH:51]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCc1ccn(Cc2cccc(F)c2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccn(Cc2cccc(F)c2)c1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
6-chloro-nicotinic acid (100 mg, 0.58 mmol), triethylamine (0.194 mL, 1.39 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (308 mg, 0.696 mmol) were dissolved in N,N-dimethylformamide (3 mL), C-(1-(3-fluoro-benzyl)-1H-pyrrol-3-yl)-methylamine (142 mg, 0.695 mmol) described in Preparation Example 59 was added, and the solution was stirred for 15 hours 10 minutes at room temperature. After the reaction was completed, the reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then the solution was concentrated, the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1), and the title compound (0.14 g, 0.39 mmol, 67%) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:46])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[C:36]([CH2:37][O:38]C3CCCCO3)=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:38][CH2:37][C:36]1[N:32]([C:28]2[CH:27]=[C:26]([C:25]3[CH2:24][C:23](=[O:46])[NH:22][C:9]4[CH:10]=[C:11]([C:20]#[N:21])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[N:33]=[N:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(cc1N1CCOCC1)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2

Procedure:
The title compound was prepared from (RS)-[4-cyano-5-morpholin-4-yl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M41) (0.36 g, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (152 mg, 61%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:24][C:23]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([OH:20])[CH:22]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCCl
Yield: 67.1 %

Procedure:
By using the above method, starting with 3 g of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 1.37 g of 3-hydroxy-4-methyl-aniline, and 1.2 g of pyridine hydrochloride in 31 ml of 2-ethoxyethanol, 2.6 g of the title compound was obtained as a crystalline solid: mass spectrum (electrospray, m/e) M+H 383.9.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[C:20]([CH3:21])=[N:19][C:18]([CH3:22])=[C:17]([CH3:23])[N:16]=2)=[CH:9][CH:8]=1)C>O>[CH3:21][C:20]1[C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:24])=[O:5])=[CH:12][CH:11]=2)=[N:16][C:17]([CH3:23])=[C:18]([CH3:22])[N:19]=1
Reactant: CCOC(=O)c1ccc(OCc2nc(C)c(C)nc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(C)c(COc2ccc(C(=O)O)cc2)nc1C
Yield: 89.8 %

Procedure:
Adding water (20 mL), NaOH (0.14 g, 3.5 mmol) into a 100 mL round-bottom flask, stirring to dissolve, then adding 95% alcohol (20 mL), 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)benzoic acid ethyl ester (0.90 g, 3.0 mmol), stirring under room temperature to react for 4 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.4, Rf of product=0), distilling out the alcohol under reduced pressure, adjusting pH of the reaction solution to 4-5 with 6.0M HCl while keeping the reaction solution cool to separate out solid, filtering, washing the solid with cool water for three times, processing with vacuum filtration, recrystallizing with anhydrous alcohol, drying under 70° C. for 8 hours to obtain 0.73 g white crystalloid of 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)benzoic acid, wherein a yield is 89.8%, m.p. 179-181° C.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:44][C:43]2[C:38](=[C:39]([O:51]C)[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42]=2[O:45]C)[CH2:37]1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:37][C:38]2[C:39](=[O:51])[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42](=[O:45])[C:43]=2[CH2:44]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCCCCCC1(C(=O)OCC)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
A water (1 ml) solution of CAN (342 mg, 0.624 mmols) was dropwise added to an acetonitrile (2 ml) solution of ethyl 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoate (100 mg, 0.208 mmols), with cooling with ice. The reaction mixture was stirred for 15 minutes and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane only to hexane:ethyl acetate=4:1) to obtain the entitled compound (69 mg) as an oil.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:17]([O:19]CC)=O)[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:8]=2[N:9]=1.[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CCOC(C)=O.O>[Br:3][C:4]1[CH:5]=[C:6]([C:17]([NH:22][CH2:23][C:24]2[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])=[O:19])[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16]3)[C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCC2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Aqueous NaOH (5 equivalent) was added to a solution of ethyl 6-bromo-1-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equivalent) in EtOH (10 times by volume) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using EtOAc; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was, then, dissolved in DMSO (10 times by volume) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (2 equivalents) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equivalents) was added to it and stirring was continued for 5 to 16 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by ether wash to provide the desired intermediate.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15]Br.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:24]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)[CH2:15]2
Reactant: COC(=O)c1c(CBr)cc(F)cc1C(F)(F)F
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(cc(F)cc2C(F)(F)F)CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A mixture of 4-fluoro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.100 g, 0.32 mmol), 4-chloro-benzylamine (0.051 mL, 0.42 mmol), and K2CO3 (0.088 g, 0.64 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-2-(4-chloro-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.048 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.75 (s, 2H) 7.24-7.51 (m, 6H). GC-MS: m/z 343 (M)+, 322 (M−21)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CCN(C(=O)C5CC5)CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.066 mmol) in THF was added cyclopropyl carbonyl chloride (5 μL, 0.04 mmol). The mixture was stirred at room temperature for ten minutes. The reaction mixture was then concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-(cyclopropanecarbonyl)piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=521)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:1]
Reactant: CN(C[C@]1(c2ccccc2)C[C@H]1CO)S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C[C@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Yield: 68.1 %

Procedure:
N-{[(1R,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide (600 mg, 1.82 mmol), accessed via the method of preparation 7B, was dissolved in 18 mL DCM with 270 uL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (1.23 g, 2.90 mmol, 1.6 eq) at ambient temperature for 16 h. The reaction mixture was diluted with 42 mL diethyl ether and treated with 22 mL 1N NaOH at ambient temperature for 15 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted successively with DCM, EtOAc/hexanes (1:4)) to the title product (410 mg, 1.24 mmol, 69%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=6.7 Hz, 1H), 7.65 (m, 2H), 7.55 (m, 1H), 7.47 (m, 2H), 7.31-7.23 (m, 5H), 3.50 (d, J=14.3 Hz, 1H), 3.09 (d, J=14.3 Hz, 1H), 2.52 (s, 3H), 2.15-2.08 (m, 1H), 1.93 (m, 1H), 1.76-1.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].COB(OC)OC.Br[C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C([Li])CCC.O1CCCC1.O.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: Fc1c(Cl)cc(I)cc1Cl
Reactant: C=C(Br)C(F)(F)F
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 67.4 %

Procedure:
In a solution of 2.00 g of 3,5-dichloro-4-fluoro-iodobenzene and 0.61 g of tert-butylmethyl ether in 18 mL of hexane, 5.3 mL of n-butyl lithium (1.54M hexane solution) was added dropwise at −10° C. with stirring, and stirred at the same temperature for 30 minutes. Then, a solution of 0.57 g of trimethoxyborane in 7 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was stirred at the same temperature further for 30 minutes and then the temperature was raised to room temperature. Then, in the reaction mixture, 1.80 g of 2-bromo-3,3,3-trifluoropropene, 1.90 g of potassium carbonate, 10 mL of water and 0.005 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ilidene (1,4-naphthoquinone) palladium (0) dimmer were added, and stirred under nitrogen atmosphere at 60° C. for 15 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and the organic phase was collected and the aqueous phase was extracted with 30 mL of ethyl acetate twice. The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 1.20 g of the aimed product as yellow oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:28])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:19]=2)=[CH:5][CH:4]=1.[CH2:29]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]([OH:44])=[O:43])=[CH:34]1)[CH2:30][CH2:31][CH3:32]>[Pd]>[CH2:29]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]([OH:44])=[O:43])=[C:34]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:28])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:19]=2)=[CH:5][CH:4]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCn1cc(C(=O)O)c2ccccc21
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CBr)cc2)n1
Agent: [Pd]
Product: CCCCn1c(Cc2ccc(-c3ccccc3-c3nnn(C(C)(C)c4ccccc4)n3)cc2)c(C(=O)O)c2ccccc21

Procedure:
reacting the 4-bromomethyl-2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl with 2-transmetalated 1-but-1-yl-1H-indole-3-carboxylic acid in the presence of phosphinated palladium catalyst to give 1-butyl-2-[2'-(2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-indole-3-carboxylic acid; and