Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1F
Yield: 76.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.053 g (77%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(N)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A mixture of 4,6-dichloro-pyrimidin-2-yl-amine (3.3 g, 20 mmol), p-tolylamine (3.4 g, 32 mmol) and N,N-diisopropylethylamine (12 ml) in ethanol (150 ml) was heated under reflux for 40 hours. After cooling to room temperature, filtration provided 6-chloro-N*4*-p-tolyl-pyrimidine-2,4-diamine (2.8 g, 60% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH3:2].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([O:10][C:15](=[O:16])[CH2:14][C:12]#[N:13])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(O)CC(=O)OCC
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(CC(=O)OCC)OC(=O)CC#N

Procedure:
A mixture of 100.14 g of ethyl-3-hydroxyhexanoate, 63.75 g of cyanoacetic acid, and 4.58 g of 4-dimethylaminopyridine (DMAP) in 625 ml of CH2Cl2 was stirred in a 2 L three-neck round bottom flask equipped with a mechanical stirrer. About 31 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (154.75 g in 250 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13].[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13])(=[O:23])[CH3:22]
Reactant: Cc1cccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1N
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(C(=O)c2ncccc2C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(3-methylpyridine-2-carbonyl)indole (Example 367) and acetyl chloride. m.p.: 173-175° C. (recrystallized from ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([CH2:32][O:33]C(=O)C)[O:29][N:28]=3)=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([CH2:32][OH:33])[O:29][N:28]=3)=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCCCC1N(Cc1ccc(-c2noc(CO)n2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
A solution of 0.03 g (0.05 mmol) acetic acid 3-(4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-[1,2,4]oxadiazol-5-ylmethyl ester in 1 ml tetrahydrofuran was stirred with 0.2 ml (0.2 mmol) 1 molar aqueous sodium hydroxide for 3 hours at room temperature. Water and aqueous hydrochloric acid was added to reach pH 1. Extraction with ethylacetate, drying with sodium sulfate, filtration and removal of the solvent by distillation yielded 0.02 g (98%) 4-chloro-N-[4-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=491.0 (MH+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCC=C(C)C)cc1
Yield: 83 %

Procedure:
A mixture of 4-hydroxybenzoic acid, methyl ester (17.0 mL, 66 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), 1-bromo-3-methylbut-2-ene (12.0 g, 79 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and potassium carbonate (23.0 g, 164 mmol) in DMSO (25 mL) was stirred at room temperature for 24 hours. EtOAc (150 mL) was added, and the mixture was washed with water (25×3 mL) and brine (25×2 mL) and dried over MgSO4. The solvent was removed, and the product was purified by CombiFlash® silica gel column chromatography, eluent with hexane/EtOAc, 90/10 to give T45.1 (12.0 g, yield 83%). 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 5.42-5.58 (1H, m), 4.57 (2H, d, J=6.8 Hz), 3.89 (3H, s), 1.81 (3H, s), 1.76 (3H, s).
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH3:35])[CH2:4][O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:18][C:17](=[O:19])[N:16](CC3C=CC(OC)=CC=3OC)[S:15]2(=[O:32])=[O:31])=[CH:9][CH:8]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:34]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6](=[O:33])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[CH2:18][C:17](=[O:19])[NH:16][S:15]2(=[O:31])=[O:32])=[CH:11][CH:12]=1)[CH3:35]
Reactant: CCC(CC)COC(=O)c1ccc(CN2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)COC(=O)c1ccc(CN2CC(=O)NS2(=O)=O)cc1

Procedure:
A solution of the title C compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid 2-ethyl-butyl ester (230 mg, 0.456 mmol) and 2 mL of TFA in 6 mL of CH2Cl2 is stirred at RT overnight. The solvent is evaporated and the residue is treated with MeCN and filtered. The filtrate is concentrated and the residue is treated with Et2O, filtered and the Et2O is evaporated to give 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2-ethyl-butyl ester as a light pink colored solid: [M−H]−=353.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=5)[CH2:29][CH2:30]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-pyridin-2-yl-piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=449.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[C:24](Cl)[N:23]=1>CN1C(=O)CCC1>[Cl:21][C:22]1[N:23]=[C:24]([N:15]2[CH2:14][CH2:13][CH:12]([N:9]3[CH2:10][CH2:11][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=4[NH:7][C:8]3=[O:18])[CH2:17][CH2:16]2)[CH:25]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:27]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)n(C)c12
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(Cl)n3)CC1)C(=O)N2

Procedure:
0.41 g (1.5 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 0.20 g (0.49 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred in 3 mL NMP for 3 h at 120° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3=[N:14][C:15]([CH3:22])=[C:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Br-].[H-].[Na+].O.[CH:27]([O:29][CH3:30])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3=[N:14][C:15]([CH3:22])=[C:16]([C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:27][O:29][CH3:30])[N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COC=O
Reactant: COC(=O)Cc1c(C)nc2sc(-c3ccc(OC)cc3)nn12
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC=C(C(=O)OC)c1c(C)nc2sc(-c3ccc(OC)cc3)nn12
Reaction time: 8 h

Procedure:
A solution of 10 g of 2-(4-methoxyphenyl)-5-methoxycarbonylmethyl-6-methylimidazolo-[2,1-b]-1,3,4-thiadiazole in 50 cm3 of methyl formate is dripped into a solution of 1.8 g of sodium hydride bromide in 10 cm3 of anhydrous dimethylformamide (DMF). The solution is left under agitation overnight at ambient temperature and is then poured into water and extracted twice with ethyl acetate.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[OH-].[K+]>CO>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[C:2]1[C:3](=[O:9])[CH:4]2[CH2:7][CH2:8][N:1]1[CH2:6][CH2:5]2
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2Cl)N2CCC1CC2

Procedure:
1-Azabicyclo[2.2.2]octan-3-one (3.86 g) was heated at reflux with 2-chlorobenzaldehyde (8.33 ml), potassium hydroxide (0.4 g) and methanol (60 ml) under nitrogen for 2.5 hours. The volatiles were removed in vacuo and the residue washed with sodium hydrogen carbonate. This was extracted (×4) with dichloromethane. The organic layer was washed with water and dried (MgSO4). The dichloromethane was removed in vacuo and the residue recrystallised from methanol-dichloromethane, to afford the title compound as yellow crystals:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][NH:11][C:10]1[C:12]([F:17])=[CH:13][C:14]([Br:16])=[CH:15][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Nc1c(F)cc(Br)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1c(F)cc(Br)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.6 g (8.78 mmol) of 2-benzyloxy-4-bromo-6-fluoroaniline and 3.03 g (21.96 mmol) of potassium carbonate in 20 mL DMF in an oil bath at 60° C. is added 1.48 g (9.67 mmole) of methyl bromoacetate. The mixture is stirred at 60° C. for 2 h. HPLC analysis indicated that the reaction is 38% complete. Additional methyl bromoacetate equal to the molar amount of unreacted starting material is added and the mixture is stirred at 60° C. for 2 h. This process is repeated until the starting material is nearly consumed. The mixture is allowed to cool then is poured into water. The mixture is extracted with ethyl acetate and the organic phase is washed 3× with water. The organic solution is dried over sodium sulfate and the solvent is removed under reduced pressure. The residual dark oil is purified by flash chromatography using methylene chloride to elute the product as a dark oil. This is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[H-].[Na+].C1(C)C=CC(S(O[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O)=CC=1>CN(C)C=O>[C:34]([O:33][C:31]([NH:30][CH2:29][CH2:28][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)cccc2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (42.9 g, 211 mmol), 60% sodium hydride (9.29 g, 232 mmol) and N,N-dimethylformamide (300 ml) was stirred at room temperature for 1 hour. A solution of 2-tert-butoxycarbonylaminoethyl 4-toluenesulfonate (86.6 g, 275 mmol) in N,N-dimethylformamide (200 ml) was added dropwise and the resulting mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/97) to obtain 24.4 g of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(OCC)(=O)C>[C:24]([C:23]1[CH:22]=[C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 35.4 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 6 ml of water and 1 ml of ethyl acetate in place of the methanol, and 118 mg of 3-aminobenzonitrile in place of the 3-(tert-butyl)aniline. 120 mg of N-(3-cyanophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.Br.Br.Br.[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][NH:40][CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]>>[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][N:40]([CH2:11][C:3]6[CH:2]=[N:1][C:10]7[C:5]([CH:4]=6)=[CH:6][CH:7]=[CH:8][CH:9]=7)[CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3cnc5ccccc5c3)C4)n[nH]c2c1
Yield: 20.9 %

Procedure:
The title compound was prepared from quinoline-3-carbaldehyde (31 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method B to afford 14.3 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[OH:10]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(N)cc1Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a 0° C. mixture of 3-bromo-4-methyl aniline (5 g; 27 mmol) and H2SO4 (5.5 mL of a 16 M solution) in H2O (7.5 mL) was added dropwise a solution of aqueous NaNO2 (1.93 g; 28 mmol in 7.5 mL H2O). The reaction was stirred at 0° C. for 30 min, then was heated at 50° C. for 2 h, then was cooled to RT and extracted with EtOAc (2×). The combined organic extracts were washed with H2O, dried (Na2SO4) and concentrated in vacuo to give 3-bromo-4-methyl phenol (1.72 g; 34%) as an oil. This phenol was converted to 3-bromo-4-methyl phenyl chloroformate (1.9 g; 82%) using the same procedure (phosgene/dimethylaniline/heat) as for 3-fluoro-4-methyl phenyl chloroformate above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:29]Br>O1CCOCC1.O>[Br:29][C:19]1[NH:20][C:21]2[C:17]([N:18]=1)=[C:16]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[N:15]=[C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:22]=2
Reactant: COc1ccc(CCNc2nc(N3CCOCC3)c3nc[nH]c3n2)cc1OC
Reactant: BrBr
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCNc2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl) amine (1.16 g, 3 mmol) in dioxane (75 mL) was added bromine (0.180 mL, 3.3 mmol) in dioxane (5 mL) dropwise over a period of 1 hour. The mixture was stirred at room temperature for additional 4 hours and diluted with water (25 mL) and extracted with EtOAc. The organic phase was washed with brine, water, dried over Na2SO4. The solvent was evaporated in vacuo and solid was washed with methanol to give (8-bromo-6-morpholin-4-yl-9H-purin-2-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine as a white solid (1.05 g, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:6].[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[CH:16]=[C:15]([NH:17][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][CH3:22])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COc1ccccc1C(=O)Nc1cc(N)ccc1C(=O)O
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC)c1

Procedure:
By the procedure similar to that described in Example 23, 2-(2'-methoxybenzamido)-4-aminobenzoic acid and 2-methoxybenzoylchloride were reacted and treated to obtain crude crystals. Recrystallization from aqueous alcohol gave 2,4-bis(2'-methoxybenzamido)-benzoic acid having a melting point between 232° - 233°C which was identical to that obtained in Example 10.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29](=[O:35])[C:30]([O:32][CH2:33][CH3:34])=O.[C:36]([O:44][CH3:45])(=[O:43])[C:37]#[C:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)CCl>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]1[C:29](=[O:35])[C:30]([O:32][CH2:33][CH3:34])=[C:38]([C:39]([O:41][CH3:42])=[O:40])[CH:37]1[C:36]([O:44][CH3:45])=[O:43]
Reactant: CCOC(=O)C(=O)Nc1ccc(F)cc1F
Reactant: COC(=O)C#CC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCOC1=C(C(=O)OC)C(C(=O)OC)N(c2ccc(F)cc2F)C1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a stirred solution of triphenylphosphine (629 mg, 2.40 mmol) and Intermediate 11A (458 mg, 2.00 mmol) in ClCH2CH2Cl (1 mL) was added dimethyl but-2-ynedioate (0.26 mL, 2.1 mmol) drop wise at rt. The reaction mixture was stirred at 80° C. in a capped vial for 18 h. The reaction mixture was allowed to cool to rt, loaded on to a 40 g silica gel column and purified with 0-100% EtOAc/Hex to give Intermediate 11B (560 mg, 1.58 mmol, 79.0% yield) as a slightly tan viscous oil. HPLC/MS (Method L) RT=1.77 min, [M+H]+ 356.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10]([C:13]1[C:21]2[O:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:26][CH2:27][CH2:28][CH2:29]Br)[CH2:11][CH3:12]>>[CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[N:4]([CH2:29][CH2:28][CH2:27][O:26][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([C:22]([F:24])([F:25])[F:23])=[N:19][O:20][C:21]=3[C:13]=2[CH2:10][CH2:11][CH3:12])[C:3]1=[O:8]
Reactant: CC1(C)CC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)CC(C)(C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3,3-Dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione was prepared as for Example 10 from 3,3-dimethylpyrrolidine-2,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:17]([NH:16][CH2:15][CH2:14][CH2:13][Cl:12])=[O:18])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C=NCCCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)NCCCCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of 4-tert-butylaniline (1.0 g, 1.07 mmol) in 5 mL toluene was added 3-chloropropylisocyanate (0.69 mL, 6.70 mmol). The reaction was allowed to stir at ambient temperature for 16 h. The reaction was partitioned between saturated NaHCO3 and ethylacetate. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 1-(4-tert-butylphenyl)-3-(3-chloropropyl)urea (31%). LCMS [M+H]+=269.2.