Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:31]([O:33][CH3:34])=[O:32])[CH3:10].O[CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C@H:9]([O:11][C:12]2[CH:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][C:24]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:25][C:20]=4[N:19]=[CH:18]3)[S:14][C:13]=2[C:31]([O:33][CH3:34])=[O:32])[CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a slurry of methyl 3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 25, 0.18 g, 0.35 mmol) and 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (0.21 g, 1.0 mmol) in DCM (10 mL) was added triphenylphosphine (0.18 g, 0.70 mmol) and di-tert-butylazodicarboxylate (0.16 g, 0.70 mmol). The clear, yellow solution was stirred for 1 h, and then silica gel (3 g) was added. The volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 50% EtOAc:CH2Cl2) to give 0.20 g (0.29 mmol) of 1,1-dimethylethyl 4-[(2-chloro-3-{(1R)-1-[(2-[(methyloxy)carbonyl]-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-3-thienyl)oxy]ethyl}phenyl)oxy]-1-piperidinecarboxylate which was then dissolved in 5 mL of DCM and TFA (1 mL, 5.9 mmol) was added. After 1 h the volatiles were evaporated under reduced pressure and the residue was dissolved in a solution of 7 N ammonia in MeOH (10 mL). The mixture was heated in a sealed tube to 80° C for 40 h and then cooled to rt. Silica (1 g) was added, the volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium hydroxide; DCM) to afford 0.14 g (69%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.42 (d, J=8.79 Hz, 1H), 7.30 (m, 2H), 7.15 (d, J=7.87 Hz, 1H), 7.10 (d, J=7.87 Hz, 1H), 6.97 (s, 1H), 6.05 (q, J=6.29 Hz, 1H), 4.56 (m, 3H), 3.06 (m, 2H), 2.69 (m, 2H), 1.95 (m, 2H), 1.77 (d, J=6.23 Hz, 3H), 1.71 (br m, 2H); MS (ESI): 581 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]2[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:15]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]2[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:15]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (1.39 g) in tetrahydrofuran (30 ml) was added potassium tert-butoxide (437 mg) under nitrogen atmosphere at 0° C. After the mixture was stirred at 0-5° C. for 1.5 hours, to this was added a solution of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (500 mg) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 4 hours and stood at room temperature overnight. Insoluble materials were filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel using dichloromethane as an eluant to give colorless crystals of 3-[2-(2-methylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (186 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Br.Br[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: BrCc1cccnc1
Agent: Br
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1Cc1cccnc1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:17]([Br:22])[N:18]3[CH3:21])=[CH:14][CH:13]=2)=[O:11])[CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].C(O)(=O)C>C(O)CC.O>[Br:22][C:17]1[N:18]([CH3:21])[C:19]2[C:15]([C:16]=1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:14][CH:13]=[C:12]([C:10]([NH:9][C:5]1([C:3]([OH:4])=[O:2])[CH2:8][CH2:7][CH2:6]1)=[O:11])[CH:20]=2
Reactant: COC(=O)C1(NC(=O)c2ccc3c(C4CCCC4)c(Br)n(C)c3c2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(Br)c(C2CCCC2)c2ccc(C(=O)NC3(C(=O)O)CCC3)cc21
Temperature: 89 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-[(2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid methyl ester (20.00 g, 46.15 mmol) in n-propanol (100 mL) and water (100 mL) was added 50% NaOH (4.06 g, 50.77 mmol). The mixture was heated at 89° C. until no starting material was left (0.5 h). The clear solution was cooled to 50° C. and acetic acid (4.23 mL, 73.85 mmol) was added dropwise to adjust the pH to 5-6. The product was precipitated as a white solid. The suspension was brought to reflux for 0.5 h and then allowed to cool to room temperature in no less than 1 h. The solid was collected by filtration, washed by 1:1 water/n-propanol (100 mL) and water (200 mL). The 1-[(2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino}-cyclobutanecarboxylic acid, obtained as a white solid was dried under vacuum until constant weight (17.78 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.CO>C(OCC)C>[Cl-:1].[C:14]([C:15]1[CH:16]=[N+:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH:18]=[CH:19][CH:20]=1)(=[O:21])[NH2:22]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC(=O)c1cccnc1
Solvent: CCOCC
Solvent: CO
Product: NC(=O)c1ccc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of 20 g (98.7 mmol) of 1-chloro-2,4-dinitrobenzene and 8 g (65.5 mmol) of nicotinamide was gradually heated to 100° C., then stirred at that temperature for one hour. The mixture was cooled to ambient temperature and 100 mL of anhydrous methanol were added. The resultant solution was poured into 400 mL of anhydrous ethyl ether, with vigorous stirring. The solvent was removed by decantation and the residual precipitate was dissolved in 100 mL of methanol. The resultant solution was poured into 400 mL of anhydrous ethyl ether, the solvent was again removed by decantation and the solid residue was dissolved in 200 mL of water. The aqueous solution was refluxed with active charcoal for 30 minutes, then filtered. The filtrate was evaporated and dried in vacuo over phosphorus pentoxide to give 14.7 g (69.2%) of the title compound of the formula ##STR80##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(N)c(Cl)cc1Cl
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(Cl)cc1Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,4-dichloro-5-methoxyaniline (44 mg, 0.232 mmol) similar to Example 117 and isolated as a brown solid (9 mg, 11%). 1H NMR (CDCl3): 9.64-9.63 (m, 1H), 8.76-8.70 (m, 2H), 8.12 (s, 1H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 6.95 (s, 1H), 4.00 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1.CCOCC>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1
Reactant: OCc1nccc(N2CCOCC2)n1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1nccc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (3.4 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-4-morpholinopyrimidine in chloroform (30 ml) cooled in an ice bath. The mixture was allowed to warm to room temperature and left to stand for a further 1.5 hours. The solution was reduced to low volume, and ether added with stirring to give 2-chloromethyl-4-morpholinopyrimidine hydrochloride (3.8 g) as a crystalline solid, m.p. 214°-6°.
Reaction SMILES: BrC1C(O)CCCN1C(=O)[C@H](C(C)C)NC(OC(C)(C)C)=O.C(OC(=O)C)(=O)C.[C:30]([O:33][C@H:34]1[C@H:39]([Br:40])[CH2:38][CH2:37][N:36]([C:41](=[O:54])[C@@H:42]([CH:51]([CH3:53])[CH3:52])[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:35]1)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:33][C@@H:34]1[C@@H:39]([Br:40])[CH2:38][CH2:37][N:36]([C:41](=[O:54])[C@@H:42]([CH:51]([CH3:52])[CH3:53])[NH:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:35]1)(=[O:32])[CH3:31]
Reactant: CC(=O)O[C@@H]1CN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)CC[C@H]1Br
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC(O)C1Br
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1CN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)CC[C@@H]1Br

Procedure:
0.57 g of bromo-N—(N-BOC-valyl)-piperidin-3-ol, dissolved in pyridine, is treated with 0.4 ml of acetic acid anhydride, the mixture obtained is stirred and a mixture of 3(R*)-acetoxy-4(R*)-bromo-N—(N-BOC-(R)-valyl)-piperidine (COMPOUND A) and 3(S*)-acetoxy-4(S*)-bromo-N—(N-BOC-(R)-valyl)-piperidine (COMPOUND B) is obtained and is separated by chromatography.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:8][C:7]=2[CH:31]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[CH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[CH:8][C:7]=2[CH:31]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(C=Cc2cc3cc(Br)ccc3o2)cc1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
91.5 g of (5-bromo-2-benzofuranyl)methyltriphenylphosphonium chloride and 25 g of p-anisaldehyde were dissolved in a mixture solvent of 180 ml of tetrahydrofuran and 180 ml of ethanol. With stirring at room temperature, 27.58 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the above solution, and the mixture was stirred for 18 hours. Thereafter, the reaction solution was concentrated to collect precipitated crystals by filtration, thereby obtaining 32.8 g of 5-bromo-2-[2-(4-methoxyphenyl)vinyl]benzofuran as one of the stereoisomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]#[N:49].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C:48]#[N:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Reactant: N#CCBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CC#N)CCC3)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A solution of 2.50 g (4.05 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)] and 0.968 g (8.10 mmol, 2.0 equiv.) of bromoacetonitrile in 15 ml of toluene and 2 ml of N-methyl pyrrolidone was treated with 2.88 g (20.27 mmol, 5.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was stirred for 18 h at 50° C., allowed to cool to room temperature, poured into 100 ml of an ice/water mixture and extracted three times with 200 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 10:1 v/v mixture of dichloromethane and ethyl acetate as eluent to yield 2.28 g (3.48 mmol, 85.9% of theory) of (3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 656 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:15]2[O:17][CH2:18][CH2:19][F:20])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([C:14]2[C@@H:15]([O:17][CH2:18][CH2:19][F:20])[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-((3S,3aR,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(2-fluoroethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (30 mg, 0.0664 mmol) in THF (4 mL) at 0° C. was added TBAF (0.13 mL, 0.132 mmol, 1M Solution in THF) and stirred for 1 h at room temperature. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Crude product was purified by preparative TLC method using 2% methanol in DCM as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[K].[CH2:36]([NH:43][S:44](=[O:47])(=[O:46])[NH2:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:5]=[C:6]([NH:45][S:44](=[O:46])(=[O:47])[NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1Cl
Reactant: NS(=O)(=O)NCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
4-[4,6-Dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carbonitrile (3.2 g) was dissolved in DMSO (20 ml), N-ethyidiisopropylamine (1.7 ml) and benzylsulfamic acid amide potassium salt (3.52 g) was added. The mixture was stirred for 18 h at rt, poured onto ice/water, acidified with solid citric acid and the precipitate was filtered off and recrystallized form EtOAc to give benzylsulfamic acid [6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (4.17 g). LC-MS: tR=5.55; [M+H]+=523.29.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[F:8][C:5]1[CH:6]=[CH:7][C:2](=[NH:1])[N:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(F)cn1
Product: CCOC(=O)Cn1cc(F)ccc1=N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-amino-5-fluoro pyridine (2.0 g, 17.84 mmol) was added ethyl bromoacetate (6.92 mL, 62.4 mmol). The resulting mixture was stirred at room temperature for 18 hours, then filtered. The solids were collected, washed with dichloromethane, and dried under reduced pressure to afford the title compound: LCMS m/z 199.00 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.05 (s, 1H), 7.93-7.90 (m, 1H), 7.14-7.12 (m, 1H), 5.02 (s, 2H), 4.25 (t, J=7.1 Hz, 2H), 1.27 (q, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[NH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl>CO.C(OCC)(=O)C>[F:8][C:2]([F:1])([F:7])[C:3]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:4]
Reactant: COC(=O)C(F)(F)F
Reactant: NCC(=O)O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)C(F)(F)F
Reaction time: 18 h
Yield: 86.9 %

Procedure:
Methyl trifluoroacetate (804 μL, 7.99 mmoles) and triethylamine (928 μL, 6.66 mmoles) were added to a suspension of glycine (500 mg, 6.66 mmoles) in methanol (2.5 mL). After the mixture was stirred vigorously for 18 h, 1 N HCl was added dropwise until the a pH of 2 was obtained. The reaction was added to ethyl acetate (30 mL) was washed with 1 N HCl (2×10 mL), dried over MgSO4, and concentrated in vacuo to yield the amide as a white solid (991 mg, 5.79 mmoles, 87%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][NH2:19].CO>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-Dichloro-3-nitropyridine (2.0 g, 10 mmol) and sodium carbonate (2.8 g, 25.9 mmol) were added to a round bottom flask under nitrogen, and suspended in ethanol (100 mL). Methylamine in methanol (7.8 mL, 16 mmol, 2M) was then added and stirred at room temperature for 3 hours. The yellow solution was concentrated, and then re-dissolved in ethyl acetate followed by washing with sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The yellow solid was then re-dissolved in ethanol and recrystallized to give 6-chloro-N-methyl-3-nitropyridin-2-amine (28-1) as a yellow solid. HRMS (M+H)+: observed=188.0216, calculated=188.0221.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:5].[Cl-:12].[NH4+:13]>CO>[ClH:12].[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4](=[NH:13])[NH2:5])[N:7]=1
Reactant: N#Cc1cccnn1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1cccnn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
Sodium methoxide (25% w/v in methanol, 0.3 ml, 1.3 mmol) was added in one portion to a stirred solution of 3-cyanopyridazine (2.4 g g, 22.9 mmol) (Ref. Heterocycles, 1986, 24(3), 793) in methanol (10 ml). The resulting mixture was stirred at room temperature for 16 hours. Ammonium chloride (2.45 g, 45.8 mmol) was added to the reaction mixture, which was then stirred for 30 minutes before being ultrasonicated for a further 15 minutes. A fine, yellow precipitate was observed after this time. The solvent was evaporated under vacuum and the residue was suspended in ethanol (150 ml) and heated to reflux for 5 minutes. The hot mixture was filtered (gravity) to remove unreacted ammonium chloride and sodium chloride and was then cooled to room temperature. A pale yellow, crystalline solid formed upon cooling and this was isolated by suction filtration to give the title compound (2.03 g), m.p. 234°-241° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[C:30]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[C:30]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH3:3])=[N:5]2
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)OCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (418 mg, 1.56 mmol) and benzyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (500 mg, 1.74 mmol) were dissolved in tert-butanol (8 ml) and DIEA (2 ml, 11.45 mmol) was added. After stirring the mixture at 80° C. for 12 h, the solvent was evaporated under reduced pressure and the residue was suspended in water, basified with sodium carbonate and extracted with AcOEt (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 560 mg (66% yield) of the title compound as a white solid. Purity 96%.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([Br:16])[N:6]=1)=[O:4].[CH3:17][S:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[CH3:17][S:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([Br:16])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: CSc1ccccc1CN
Product: CSc1ccccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Temperature: 25 °C

Procedure:
To a 25 mL round bottomed flask with a stirring bar, reflux condenser and a nitrogen inlet was added 5-bromo-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid methyl ester (0.511 g, 1.81 mmol) dry toluene (12.5 mL) and 2-methylthiobenzylamine (0.346 g, 2.26 mmol). This mixture was heated at reflux for 24 h. The mixture was cooled to ambient temperature and the toluene was removed in vacuo. The residue was triturated with a little Et2O/hexane, collected on a frit and dried in vacuo to give 8-hydroxy-5-bromo-[1,6]naphthyridine-7-carboxylic acid 2-methylsulfanylbenzylamide as a crystalline solid.