Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][Cl:8])=[CH:5][S:4][C:3]=1[C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH2:28])=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:9]([C:3]2[S:4][CH:5]=[C:6]([CH2:7][Cl:8])[C:2]=2[Cl:1])=[O:10])=[CH:17][CH:18]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1scc(CCl)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.7 %

Procedure:
To a solution of 3-chloro-4-chloromethyl-2-(chlorocarbonyl)thiophene (3.1 g, 13.5 mmol) in methylene chloride (40 mL) at 0° C. was added N-(4-chlorophenyl)-2-amino-5-chlorobenzamide (3.8 g, 13.5 mmol), followed after 5 minutes by pyridine (1.6 mL, 16 mmol). The mixture was warmed to ambient temperature. After 17 hours, the mixture was concentrated of all volatiles in vacuo. The resulting solid was triturated with water and a small amount of acetonitrile and dried in vacuo to afford 5.1 g (80% yield) of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a tan powder: NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 4.8 (s, 2) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.NC1C(C(N)=O)=NC(C2C=CC(F)=CC=2)=CC=1>>[NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: NC(=O)c1nc(Cl)ccc1N
Agent: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Product: NC(=O)c1nc(-c2cccc(F)c2)ccc1N
Yield: 92 %

Procedure:
was synthesized from 3-amino-6-chloropyridine-2-carboxylic acid amide and 3-fluorophenylboronic acid in 92% yield as a white solid, using the procedure described for the synthesis of 3-amino-6-(4-fluorophenyl)-pyridine-2-carboxylic acid amide. The mass spectrum was as follows: MS (m/z): 232 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[C:20]2[C:27]([CH3:28])=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1>C(O)(C)C>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:19]1[C:20]2[C:27]([CH3:28])=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3C[C@@H](C)NC[C@@H]3C)c12
Temperature: 150 °C
Yield: 13.9 %

Procedure:
Trans-2,5-dimethylpiperazine (1 g, 8.8 mmol), N,N-diisopropylethylamine (1 ml) and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 11.9 mmol) were added to isopropanol (10 ml). The solution was heated in a microwave at 150° C. for 6 hours, then concentrated under vacuum. The material was purified by prep HPLC (Sunfire C18 30×250 mm column. 10-100% MeCN:H2O (10 mM NH4OAc), 18 min., 45 ml/min.) to give 4-(trans-2,5-dimethylpiperazin-1-yl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.30 g, 14%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[NH:39]1[CH2:44][CH2:43][CH2:42][CH:41]([C:45](O)=[O:46])[CH2:40]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:45]([CH:41]3[CH2:42][CH2:43][CH2:44][NH:39][CH2:40]3)=[O:46])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: O=C(O)C1CCCNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCCNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to it Et3N (3 equiv.) and piperidine-3-carboxylic acid (2 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:61][C:62]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH2:74])[CH2:70][CH2:69]1)=[O:67])([CH3:64])[CH3:63]>ClCCl.CN(C)C=O>[C:62]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH:74][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:18]3[N:17]=[CH:16][C:7]4[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:6]=4[N:19]=3)=[CH:22][CH:23]=2)[CH2:70][CH2:69]1)=[O:67])([CH3:61])([CH3:63])[CH3:64]
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
A mixture of 0.093 g (0.23 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11), 0.093 g (0.92 mmole) of triethylamine, 0.133 g (0.35 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.070 g (0.35 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.075 g of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([CH2:57][NH2:58])[CH2:53][CH2:52]1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:58][CH2:57][CH:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: CN1CCC(CN)CC1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN1CCC(CNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-hydroxybenzotriazole (68.1 mg, 0.504 mmol) and EDCI (97 mg, 0.504 mmol) were dissolved in DCM (Volume: 4.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig'sBase (0.132 ml, 0.756 mmol) and (1-methylpiperidin-4-yl)methanamine (100 mg, 0.780 mmol) were added. The reaction was stirred at room temperature overnight. It was diluted with water and ethyl acetate. The water layer was washed with another portion of ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting crude material was triturated with diethyl ether/ethyl acetate to afford the product as a white solid. (Yield: 83 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.77, 7.62, 7.54, 7.35-7.30, 7.21, 7.13-7.06, 6.72, 5.49, 4.38, 4.02, 2.93, 2.78, 2.42-2.30, 2.17, 1.77, 1.57, 1.45-1.02
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H][H]>C(O)C.[Pd]>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccccc12
Yield: 65.3 %

Procedure:
(R)-5-Bromo-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole (60 mg, 0.2 mmol) was dissolved in ethanol (1 mL) and hydrogenated over 10% palladium on carbon (45 mg) at 60 p.s.i. of hydrogen pressure at room temperature for 16 hours. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic phase was dried (Na2SO4), and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluting with 89:10:1 CH2Cl2 :MeOH:NH4OH) to give the title compound (28 mg). Anal. Calcd for C14H18N2 ·1/8 CH2Cl2C,75.42; H,8.18; N,12 46 Found: C,75 50; H,8 51; N,12 09. [α]25D =+60.2° (c=0.088, CHCl3).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].O.[N+]([O-])([O-])=O.[Ag+:18]>C(OCCCC)(=O)C>[O-:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1].[Ag+:18]
Reactant: CCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCCCOC(C)=O
Solvent: O
Product: CCCCCCCCCC(=O)[O-]

Procedure:
A solution of 8.6 g of capric acid in 100 ml of butyl acetate was maintained at a temperature of 5° C., to which 200 ml of water was added with stirring to form an emulsion. 50 ml of an aqueous solution of silver ammonium complex containing 8.5 g of silver nitrate (chillset at 5° C.) was added to the above emulsion over a 30 second period in order to allow the capric acid to react with the silver ion. After the removal of an aqueous phase, a silver caprate-containing butyl acetate phase was dispersed into 120 g of isopropanol solution containing 15 weight percent of polyvinyl butyral to produce a polymer dispersion of silver caprate. A composition containing the several components setforth below were added to the polymer dispersion of silver caprate in their listed order every ten minutes while maintaining the temperature at 50° C., resulting in the formation of a heat developable light-sensitive coating composition.
Reaction SMILES: Cl[C:2]1[C:3](=[O:30])[N:4]([CH:27]([CH3:29])[CH3:28])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=1[CH2:24][CH2:25][CH3:26].C(O)C>[C].[Pd].C(N(CC)CC)C>[CH2:24]([C:14]1[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=[CH:18][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]1[CH:6]=[N:5][N:4]([CH:27]([CH3:28])[CH3:29])[C:3](=[O:30])[CH:2]=1)[CH2:25][CH3:26]
Reactant: CCCc1cc(C(=O)OCC)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCc1cc(C(=O)OCC)ccc1OCCCNc1cnn(C(C)C)c(=O)c1
Reaction time: 3 h

Procedure:
A mixture comprising 0.82 g of 4-chloro-5-[3-(2-n-propyl-4-ethoxycarbonylphenoxy)propylamino]-2-i-propyl-3(2H)pyridazinone (Compound No. 64), 50 ml of ethanol, 1.5 ml of triethylamine and 150 mg of 5% palladium-carbon was subjected to hydrogenation under stirring at a temperature of from 40° to 50° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 0.58 g of the above identified compound as colorless crystals having a melting point of from 111° to 116° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[CH:8]=[N:11][C:12]1[N:16]2[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc2ncc3c(Cl)ncnc3n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
The product from Example 1a (1.24 g, 7.01 mmol) in 30 mL of THF was reacted with 5-amino-3-methylpyrazole (0.68 g, 7.01 mmol) in 10 mL of THF under an argon atmosphere by dropwise addition. Stirred at room temperature for 1 hour than added diisopropylethylamine (1.22 mL, 7.01 mmol) dropwise with stirring. Heated overnight at 60° C. Quenched with water and extracted with EtOAc washed with brine and dried over Na2SO4. Filtered and the solvent was removed under vacuum. The product was purified by silica gel chromatography eluting with EtOAc/hexane to give the title compound as a pale yellow solid (405 mg, 29%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([NH:14][CH2:15]C2C=CC=CC=2)[C@@H:8]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])([CH3:3])[CH3:2].[Br:29][C:30]1[CH:31]=[N:32]C(Cl)=[N:34][CH:35]=1.CCN(C(C)C)C(C)C>C(O)C.[Pd].CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([NH:14][C:15]2[N:32]=[CH:31][C:30]([Br:29])=[CH:35][N:34]=2)[C@@H:8]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: Clc1ncc(Br)cn1
Reactant: CC[C@@H]1C[C@H](NCc2ccccc2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCO
Product: CC[C@@H]1C[C@H](Nc2ncc(Br)cn2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 40 %

Procedure:
A solution of (2S,3S,5R)-2-benzyl-3-benzylamino-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (0.16 mmol; 61 mg) in ethanol (5 mL) is hydrogenated over 10% palladium on carbon (6 mg) at 50° C. and atmospheric pressure. After 9.5 hours, the suspension is cooled to ambient temperature and purged with nitrogen. The reaction mixture is filtered and concentrated under reduced pressure. A mixture of the obtained material (46 mg), 5-bromo-2-chloropyrimidine (0.18 mmol; 34.8 mg) and DIPEA (0.32 mmol; 41.4 mg) in DMF (0.8 mL) is stirred at 100° C. for 4 hours and then at 120° C. for 8.5 hours, and cooled to ambient temperature. The solution is diluted with brine and EtOAc. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane/EtOAc) to give (2S,3S,5R)-2-benzyl-3-(5-bromo-pyrimidin-2-ylamino)-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (28.6 mg, 40% in 2 steps); ESI-MS m/z: 447 [M++1], Retention time 2.36 min (condition A).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:13][CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)=O)=[O:12])=[CH:3]1>O=P(Cl)(Cl)Cl>[CH3:28][O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:15]1[O:12][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[N:13][CH:14]=1)[CH:26]=[CH:25]2
Reactant: COc1ccc2cc(C(=O)CNC(=O)c3cn(C)c4ccccc34)ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(-c3cnc(-c4cn(C)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Yield: 250.6 %

Procedure:
1-Methyl-N-[2-(6-methoxy-2-naphthyl)-2-oxoethyl]-1H-indole-3-carboxamide (3.68 g 2.68 mmol), prepared in the previous step, in 200 mL of POCl3 was refluxed for 4 h. As the reaction cooled to room temperature a solid precipitated. The solid was collected by filtration, rinsed with 10 mL of methylene chloride and dried under reduced pressure. The solid was then taken up in 80% CH2Cl2/CH3OH, extracted three times with 5% NaHCO3, dried (MgSO4), filtered and the solvent was removed under reduced pressure to give 3-[5-(6-methoxy-2-naphthyl)-1,3-oxazol-2-yl]-1-methyl-1H-indole (2.38 g, 68%) as a light yellow solid, mp 187-189° C. Elemental Analysis for C23H18N2O2 Calc'd: C, 77.95; H, 5.12; N, 7.90. Found: C, 77.16; H, 5.10; N, 7.77.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1S
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CSc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
2-Aminothiophenol (25 g, 0.2 mol) was reacted with 16 g sodium hydroxide (0.40 mol) and 34.8 g p-methoxybenzylchoride (0.22 mol) by the method described in Example 24. The mixture was stirred at room temperature for 16 hours. The precipitate was filtered from the reaction mixture, and recrystallised from ethyl acetate to give 23 g of the desired product as a light brown solid (47% yield). 1H NMR (60 MHz, CDCl3): 3.66 (s, 3H), 3.73 (s, 2H), 4.13 (brs, 2H), 6.3-7.3(m, 8H) ppm. TLC (50% ethyl acetate/hexane) Rf 0.80.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:17]([NH:19][C:20](=[O:21])[C:15]=12)=[O:18].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)C>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][CH:22]=[C:16]3[C:17]([NH:19][C:20](=[O:21])[C:15]=23)=[O:18])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C1NC(=O)c2c(CCCCCCCCCCCCBr)cccc21
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCCCCCCCCN3CCOCC3)cccc21

Procedure:
12-Bromododecylphthalimide (623 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[CH3:12].[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][C:15]=1[C:25]1[C:30]([F:31])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:26]=1[F:41].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:8]([C:6]1[N:7]=[C:2]([C:28]2[CH:27]=[C:26]([F:41])[C:25]([C:15]3[CH:16]=[CH:17][C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:14]=3[Cl:13])=[C:30]([F:31])[CH:29]=2)[C:3]([CH3:12])=[N:4][C:5]=1[CH3:11])(=[O:9])[NH2:10]
Reactant: COC(=O)Cc1ccc(-c2c(F)cc(B3OC(C)(C)C(C)(C)O3)cc2F)c(Cl)c1
Reactant: Cc1nc(C)c(C(N)=O)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2c(F)cc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A solution of 6-chloro-3,5-dimethylpyrazine-2-carboxamide (Intermediate A) (228 mg, 1.23 mmol) and methyl 2-(2-chloro-2′,6′-difluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl)acetate (Intermediate 2-2; 521 mg, 1.23 mmol) and potassium phosphate, tri-basic (314 mg, 1.48 mmol) in DME (15 mL), MeOH (3.75 mL) and water (3.75 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (50.3 mg, 0.06 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 80° C. for 17 hours. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and 2M HCl (50 mL), the aqueous phase was extracted with a further 80 mL of EtOAc. The organic extracts were combined, dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′,6′-difluorobiphenyl-4-yl)acetate (295 mg, 53.7%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:27][NH2:28])=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[C:26]5[C:22]=4[CH:23]=[CH:24][NH:25]5)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: NCc1ccc(F)c2[nH]ccc12
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cc[nH]c12
Temperature: 120 °C

Procedure:
A tube was charged with 53 (63 mg, 0.27 mmol), 114 (44 mg, 0.27 mmol), DIPEA (2 mL) in IPA (5 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated in vacuo and the residue was purified by preparative HPLC to afford 56 mg (57%) of I-47 as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[CH3:61][C:62]([CH3:75])([CH3:74])[CH2:63][NH:64][S:65]([CH2:68][CH2:69][NH:70][CH:71]([CH3:73])[CH3:72])(=[O:67])=[O:66]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:70]([CH2:69][CH2:68][S:65](=[O:67])(=[O:66])[NH:64][CH2:63][C:62]([CH3:75])([CH3:74])[CH3:61])[CH:71]([CH3:72])[CH3:73])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NCCS(=O)(=O)NCC(C)(C)C
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
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: CN(C)C=O
Product: CC(C)N(CCS(=O)(=O)NCC(C)(C)C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 2-isopropylamino-ethanesulfonic acid (2,2-dimethyl-propyl)-amide (0.070 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.042 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.