Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][NH2:11]>C1COCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:11][CH3:10])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. mixture 2,4,6-trichloropyrimidine (0.50 g, 2.7 mmol) in THF (3 mL) was added methyl amine (2M THF, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 30 minutes, at which time LCMS indicated the formation of the desired product. The reaction mixture was treated with water (10 mL) and extracted with EtOAc (2×10 mL). The organics were washed with brine (10 mL), dried (Na2SO4), and evacuated. The crude material was purified by column chromatography (Gradient from 0-30% EtOAc in Hexanes) to afford 180 mg (1.01 mmol, 38%) of 2,6-dichloro-N-methyl-4-pyrimidinamine and 150 mg (0.85 mmol 31%) of 4,6-dichloro-N-methyl-2-pyrimidinamine. MS (ES+) m/e 178 [M+H]+ for each.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26](=[O:33])(=[O:32])[NH:27]C(C)(C)C)[CH:21]=2)[C:8]([O:13]COCCOC)=[C:9]([CH:11]=O)[CH:10]=1)=[O:4].[ClH:34].[NH2:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[NH2:45])[C:39]([NH2:41])=[NH:40]>>[ClH:34].[C:39]([C:38]1[CH:42]=[CH:43][C:44]2[NH:45][C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([S:26](=[O:32])(=[O:33])[NH2:27])[CH:21]=4)[C:8]=3[OH:13])=[N:35][C:36]=2[CH:37]=1)(=[NH:40])[NH2:41]
Reactant: COCCOCOc1c(C=O)cc(C(=O)OC)cc1-c1cccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cccc(S(N)(=O)=O)c4)c3O)nc2c1
Yield: 39 %

Procedure:
Proceeding as in Reference 23, but substituting 3′-tert-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymethoxy)-biphenyl-3-carboxylic acid methyl ester (1.64 g, 3.42 mmol, 1.0 eq.) and 3,4-diamino-benzamidine hydrochloride (638 mg, 3.42 mmol, 1.0 eq.), gave 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-3′-sulfamoyl-biphenyl-3-carboxylic acid hydrochloride (650 mg) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.[CH:27]1[CH:28]=[CH:29][C:30]2N(O)N=[N:33][C:31]=2[CH:32]=1.C(Cl)CCl.NC1C=CC=CC=1>CCOC(C)=O.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([C:15]([NH:33][C:31]3[CH:32]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@@H]1CO[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A 5 mL vial was charged with (2S,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinecarboxylic acid (72 mg, 0.201 mmol), HOBT (29.9 mg, 0.222 mmol) and DMF (1 mL) under nitrogen. The mixture was stirred and cooled in an ice bath and then EDC (42.5 mg, 0.222 mmol) was added. After stirring 10 minutes, aniline (0.020 mL, 0.222 mmol) was added and the mixture was allowed to warm to room temperature and stir. At 2 and 4 hours, there was no change in progress. The mixture was diluted with EtOAc and washed with water, saturated NaHCO3, brine, and dried (MgSO4). After filtering, the filtrate was concentrated and the product was purified by silica gel chromatography (Analogix SF-4-g) eluting with 20-50% EtOAc—CHCl3 to afford the title compound (59 mg) as a light orange oil. LC-MS (ES) m/z=433 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution tert-butyl 2-[(3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]acetate, 2b, (0.12 g, 0.26 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The crude residue was diluted with 5% MeOH/CH2Cl2 and the resulting white precipitate was filtered and washed with CH2Cl2 to afford the desired product, 577, as trifluoroacetic acid salt.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]
Reactant: NCCCCCCN1CCCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCCN5CCCC5)n4)cc3)cc12

Procedure:
Using 6-pyrrolidin-1-ylhexylamine (reference example 93e) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 536 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=3)[C:15]([O:17]C(C)(C)C)=[O:16])[O:9][N:8]=2)[CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=3)[C:15]([OH:17])=[O:16])[O:9][N:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Reaction time: 1 h

Procedure:
A solution of the product of Example 45 (180 mg, 0.56 mmol) in methylene chloride (5 mL) was stirred with trifluoroacetic acid (1 mL) at room temperature for 4 hours. It was then concentrated and the residue was stirred in water (15 mL) for 1 hour. The precipitate was collected by filtration and dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 8.28 (ddd, J=8.0, 1.5, 1.2 Hz, 1H), 8.42-8.51 (m, 2H), 8.70 (t, J=1.6 Hz, 1H), 8.83 (dd, J=5.0, 1.8 Hz, 1H), 9.28 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCl/NH3) m/z 268 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.N1CCCC1.[OH:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]>CO>[CH3:1][C:2]1([CH3:4])[CH2:22][C:21](=[O:23])[C:12]2[C:11](=[CH:16][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:13]=2)[O:10]1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccc(C(F)(F)F)cc2O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
Acetone (3.56 mL, 48.5 mmol) and pyrrolidine (8.02 mL, 97.0 mmol) were added to a solution of Example 3A in methanol (100 mL). The reaction mixture was stirred at ambient temperature for 14 hours concentrated, diluted with EtOAc (300 mL), then washed with water (100 mL), 2N HCl (2×100 mL), water (50 mL), 2N NaOH (2×100 mL), water (50 mL), and brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (8.93 g, 36.6 mmol, 75%) as a white solid. MS (ESI) m/z 245 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1conc1-c1ccc(CCCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1conc1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
Methyl 3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylate (1.46 g, 5.49 mmol) was dissolved in THF-water (2:1, 30 ml), lithium hydroxide monohydrate (922 mg, 21.97 mmol) was added, and the mixture was stirred at room temperature for 6 hours. THF was evaporated under reduced pressure, 2N hydrochloric acid was added to weak-acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.38 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:32][CH:29]2[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:27][CH2:28]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)cc2)CC1
Yield: 86 %

Procedure:
The title compound (0.51 g, 85%) was prepared as a white solid from 2′-fluoro-4′-(methylsulfonyl)-4-biphenylol (0.34 g, 1.28 mmol), N-Boc-4-piperidinemethanol (0.29 g, 1.28 mmol) and Ph3P (0.34 g, 1.28 mmol) in THF (8 mL) followed by diisopropyl azodicarboxylate (0.28 g, 94%, 1.28 mmol) in THF (2.5 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CD3OD): δ 7.85-7.70 (m, 3H), 7.54 (d, 2H, J=7.3 Hz), 7.04 (d, 2H, J=8.8 Hz), 4.15-4.05 (m, 2H), 3.90 (d, 2H, J=6.1 Hz), 3.16 (s, 3H), 2.90-2.75 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 464 (M+H).
Reaction SMILES: Cl[Sn]Cl.Cl.[Br:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([C:10]#N)=[CH:8][C:7]=1[F:15].CC[O:18]CC>O>[Br:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([CH:10]=[O:18])=[CH:8][C:7]=1[F:15]
Reactant: CCOCC
Reactant: N#Cc1cc(F)c(Br)c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: O=Cc1cc(F)c(Br)c(F)c1
Reaction time: 8 h

Procedure:
167 g (0.88 mol) of SnCl2 was added to 880 cm3 of diethyl ether, and dried HCl gas was absorbed to saturation at room temperature. 98 g (0.44 mol) of 4-bromo-3,5-difluorobenzonitrile was added all at once to this mixture, and after stirring for i hour, it was let stand overnight. The reactant was poured into 1,000 cm3 of water, and ether was distilled on a hot water bath at 50° C. The residue was extracted by adding chloroform, and after washing in water the chloroform was removed. The residue was distilled under reduced pressure (b. p. 96° C./73 mmHg) to obtain 88 g (0.40 mol) of 4-bromo-3,5-difluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)([NH:11][C:4]3[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=3[C:6]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:7])[C:13](=[O:22])[NH:14]2)=[CH:19][CH:18]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Cl)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
The mixture of 4-chloro-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (23 mg, 0.05 mmol), morpholine (26 mg, 0.3 mmol) and EDCl (15 mg, 0.08 mmol) in dichloromethane (1 mL) was stirred at room temperature for overnight. The crude was then purified with chromatography to give 22 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=530.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[N:10][C:9]=2[N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[C:24]([N:8]1[C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[S:12][C:13]=2[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(NC(=O)c3ccc(C)cc3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Nc2nc3c(s2)c(C(=O)O)cn3C(C)(C)C)cc1
Yield: 83.7 %

Procedure:
Water (50 ml) was added to a stirred suspension of 4-tert-butyl-2-(4-methyl-benzoylamino)-4H-pyrrolo[2,3-d]thiazole-6-carboxylic acid ethyl ester (4.0 g, 10.5 mmol) and lithium hydroxide (1.0 g, 42.6 mmol) in THF (105 ml). The mixture was held at reflux for 18 hours, cooled, diluted with water (200 ml), and washed with ethyl acetate. The aqueous phase was chilled, then acidified (6M HCl), with stirring, to precipitate product. The solid was filtered and dried to yield 3.14 g (84%) of the product. MS: M+H=358.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24]4([CH3:31])[NH:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24]4([CH3:31])[NH:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C4(C)NC(=O)NC4=O)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C4(C)NC(=O)NC4=O)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a solution of 5-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-5-methyl-imidazolidine-2,4-dione (57 mg, 0.1 mmol) in methanol (2 mL) was added potassium hydroxide (50% w/v in water, 0.4 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was purified directly by mass-triggered reverse-phase HPLC to afford 5-{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-5-methyl-imidazolidine-2,4-dione as a white powder (21 mg, 51%). MS: m/z 413 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 1.72 (s, 3H), 3.85 (s, 3H), 7.05 (t, 1H), 7.15 (d, 1H), 7.31 (dt, 1H), 7.49 (d, 1H), 7.51 (t, 1H), 7.57 (dd, 1H), 7.70 (d, 1H), 7.73 (d, 1H) 7.76 (s, 1H), 8.14 (d, 1H), 8.53 (d, 1H), 8.73 (s, 1H), 10.82 (s, 1H), 11.95 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11]([CH3:12])=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(Br)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Into a Round bottom flask, 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (4.00 g, 0.0164 mol) and Methylene chloride (100 mL) were added. m-Chloroperbenzoic acid (77% max)(5.14 g, 0.0229 mol) was added portion wise over 20 minutes and the reaction was stirred at room temperature for one hour. The mixture was partitioned with DCM (200 mL) and saturated NaHCO3 (200 mL). Organic extracts were washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The solid was washed with hexane to afford 3.27 grams of 7-Bromo-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow powder. 1H NMR (400 MHz, DMSO, d6) δ 9.34 (s, 1H), 7.51 (m, 1H), 7.41 (d, 1H, J=4.71 Hz), 3.43 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:45]=[CH:44][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH:36]4[C:40]([O:42]C)=[O:41])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH:36]4[C:40]([OH:42])=[O:41])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:44][CH:45]=1)=[O:11]
Reactant: COC(=O)C1CCCN1CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC5C(=O)O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate (Example 50) (68 mg, 0.11 mmol) in a mixture of THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 16 hours and poured into 30 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid as light reddish solid. Yield: 60 mg, 91%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:15])[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:39])=O)C=CC=CC=1>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH:13]([C:14]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[NH2:39])=[O:15])[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)N(N)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 18A (308 mg, 0.8 mmol, 1 eq) was dissolved in 15 mL of tetrahydrofuran. Sodium hydride (60% in oil, 38 mg, 0.96 mmol, 1.2 eq) was added, and the mixture was stirred at rt for 15 min. O-Diphenylphosphinylhydroxylamine (224 mg, 0.96 mmol, 1.2 eq) was then added, and the reaction was stirred at rt for 1 h. LC analysis indicated that the starting material had been consumed. Water was added, and the reaction was extracted with CH2Cl2. The combined organic extracts were dried and concentrated in vacuo to provide Compound 18B as a semi-solid in quantitative yield. The compound was used without further purification. LC: R.T.=3.39 min (retention time) (YMC Combiscreen ODS-A S5 column eluting with 10-90% aqueous methanol over a 4 minute gradient.)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([OH:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]1=[O:16].[H-].[Na+].[CH2:19](Br)[CH3:20].O>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([O:7][CH2:19][CH3:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]1=[O:16]
Reactant: CCBr
Reactant: CN1CC(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC1CN(C)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Yield: 82.1 %

Procedure:
Dissolved in 100 ml of dimethylformamide was 10.4 g (0.04 mole) of 1-methyl-3-(3,4-dichlorophenyl)-4-hydroxyimidazolidine-2-one. The solution was cooled to 10° C. and 2 g (0.04 mole) of sodium hydride was added to the solution with stirring. After the addition, the mixture was stirred for 30 minutes and 4.4 g of ethyl bromide was added dropwise. The mixture was stirred at room temperature for 2 hours and water was added to the reaction mixture. The mixture was extracted with chloroform and the chloroform extract was concentrated, giving 9.5 g of an oil in 82.1% yield.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OC)(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[C:1]([NH:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[S:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24](=[O:32])[N:23]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1cccc(C#N)c1)NC(=O)c1ccccc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1cccc(-c2nc(=O)c3ccccc3s2)c1)NC(=O)c1ccccc1
Temperature: 145 °C
Reaction time: 15 h
Yield: 17.1 %

Procedure:
A mixture of methyl 2-(benzoylamino)-3-(3-cyanophenyl)propionate (201 mg, 0.652 mmol), methyl thiosalicylate (165 mg, 0.981 mmol), triethylamine (0.18 mL, 1.3 mmol) and xylene (0.65 ml) was stirred at 145° C. for 15 hours under a nitrogen flow. The reaction mixture was applied to silica gel column chromatography (gradient elution with hexane-ethyl acetate from 67:33 to 50:50). The eluate was crystallized from ethyl acetate-diisopropyl ether to give the title compound (49.7 mg, 17%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:29]3[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:31][C:30]=3[O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[N:16][N:17]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:52]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:29]3[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:31][C:30]=3[O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[N:16][N:17]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:20])=[O:21])[C:18]=2[CH3:52])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)n2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
N-Butyl lithium (1.6M in hexane; 0.25 ml, 0.4 mmol) was added dropwise to a stirred, cooled (−78° C.) solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester) 240 mg, 0.33 mmol) in tetrahydrofuran (2 ml), under a nitrogen atmosphere. The mixture was stirred at −78° C. for 10 minutes, then methyl iodide (40 μL; 0.64 mmol) was added. The reaction mixture was warmed to room temperature, then partitioned between water (20 ml) and ethyl acetate (2×20 ml). The combined organic phases were dried over magnesium sulphate, then concentrated in vacuo, and purified on silica cartridge (200 mg) eluting with hexane, then hexane:diethyl ether, 1:1, then diethyl ether gave 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-5-methyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (70 mg; 29%)