Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10].[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=1[F:17])[CH3:10]
Reactant: C[C@]1(c2ccccc2F)N=C(N)COC[C@@H]1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)COC[C@@H]1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5R,6R)-6-fluoro-5-(2-fluorophenyl)-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.2 mmol) in sulfuric acid (5.0 ml) was added at 0° C. red fuming nitric acid (1.9 mmol) over a period of 20 min and stirring was continued for 30 min. The solution was dropped slowly into ice/water (60 ml), the pH was adjusted to 9 by addition of aqueous 4 N NaOH and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silica-NH2 using n-heptane/ethyl acetate to give (5R,6R)-6-fluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine as a pale yellow solid. MS (ISP): m/z=286.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[C:6]3[C:7](=[CH:13][CH2:14][NH2:15])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[O:1]1[C:5]2[C:6]3[C:7](=[CH:13][CH2:14][NH:15][C:23](=[O:25])[CH3:24])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1
Reactant: NCC=C1CCc2ccc3ncoc3c21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC=C1CCc2ccc3ncoc3c21
Reaction time: 0.25 h
Yield: 53 %

Procedure:
2-(6,7-Dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethanamine (30.0 mg, 0.148 mmol) was dissolved in tetrahydrofuran (1 mL), triethylamine (31.0 μL, 0.222 mmol) and acetic anhydride (16.8 μL, 0.178 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (19.0 mg, yield 53%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14](OC)=[S:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=[O:22])C>O1CCCC1.CN(C)C=O>[OH:22][C:8]1[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:14]=2[S:15][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=S)c1ccncc1Cc1ccccc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Oc1c(-c2ccccc2)sc2cnccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of 4.8 g (19 mmol) of methyl 3-phenylmethylthiopyridine-4-carboxylate in 10 mL of tetrahydrofuran was added to a slurry of 2.40 g (60 mmol) of 60% sodium hydride in 10 mL of N,N-dimethylformamide and the resulting mixture was stirred at 60° C. for 3 hours. The solution was poured onto ice water and acidified with glacial acetic acid. The filtrate was collected to afford 1.6 g (38%) of white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:10]=[O:11].B(F)(F)F.C[CH2:17][O:18][CH2:19]C>C(O)(=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([CH:2]2[CH2:10][O:11][CH2:19][O:18][CH2:17]2)=[O:3])[CH:5]=1
Reactant: CCOCC
Reactant: C=O
Reactant: CC(=O)c1cccnc1
Agent: FB(F)F
Solvent: CC(=O)O
Product: O=C(c1cccnc1)C1COCOC1
Reaction time: 0.67 h

Procedure:
A 60.6 g. portion of 3-acetylpyridine was combined with 54 g. of paraformaldehyde and 250 ml. of acetic acid. The mixture was cooled in an ice bath, and 184 ml. (1.5 moles) of boron trifluoride etherate was added dropwise with stirring, over a period of about 40 minutes. The temperature of the mixture ranged from 15° to 26° during the addition. The mixture was then stirred under reflux, at about 67°, for 2 hours 15 minutes, and was then cooled slightly. The volatile portions and most of the acetic acid were removed under vacuum, and the remaining mixture was rinsed with water to a large beaker and was made basic with ammonium hydroxide. The basic mixture was filtered through glass wool, and the filtrate was extracted with chloroform. The organic layer was then washed with saturated aqueous sodium chloride, and was dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to obtain 128 g. of crude product, which was recrystallized from isopropanol. The total yield was 59.1 g. of purified product, the first crop of which had a melting point of 98°-100°.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:24][C:23](=[O:25])[C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:32][CH2:33][CH:28]([NH:27][C:20]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([O:10][CH2:9][C:6]2[C:5]4[C:23](=[O:25])[CH2:24][C:2]([CH3:26])([CH3:1])[CH2:3][C:4]=4[O:8][CH:7]=2)[CH:19]=[CH:18][CH:17]=3)=[O:21])[CH2:29][CH2:30]1
Reactant: CC1(C)CC(=O)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2C1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6c5C(=O)CC(C)(C)C6)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 16 g and amine 14.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[N-:45]=[N+:46]=[N-:47].[Na+]>O.CN(C)C=O>[N:45]([CH2:15][C:13]1[N:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([O:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOc1ccc(CO)nc1OCc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(CN=[N+]=[N-])nc1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a mixture of (6-benzyloxy-5-propoxy-pyridin-2-yl)-methanol (1.09 g, 4.0 mmole) and 20 mL of N,N-dimethylformamide stirred and cooled with an ice bath to 0° C. is added triphenylphosphine (1.57 g, 6.0 mmole) followed by carbon tetrabromide (1.99 g, 6.0 mmole). This is stirred for 15 minutes maintaining temperature between 0-5°. Sodium azide is then added (781 mg, 12.0 mmole) and the reaction mixture stirred for 24 hrs at ambient temperature. The reaction mixture is diluted with water and extracted with ether. The combined extracts were dried over sodium sulfate, filtered, evaporated and the residue chromatographed on silica gel eluting with hexane/ethyl acetate to give a-clear liquid, 1.05 g, (88%); MS (ES+): m/z 299.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.ClC1C(NCC(=O)CC(C)C)=NC2C(N=1)=CC=CC=2.CS(C)=O.N(C)(C)C>CCN(CC)CC>[Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: OC(CCc1ccccc1)CNc1nc2ccccc2nc1Cl
Agent: CC(C)CC(=O)CNc1nc2ccccc2nc1Cl
Agent: CN(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(CCc1ccccc1)CNc1nc2ccccc2nc1Cl

Procedure:
3b is prepared from 2b according to the protocol described for 3a; 2b (4.7 g, 14.4 mmol), 14.4 ml DMSO, 14.4 ml Et3N, and Me3N.SO3 (4 g, 28.8 mmol). The product is purified by chromatography on a silica column, eluent: C6H12/Et2O (80:20) to give a yellow solid (4.51 g, 96%); 1H NMR (100 MHz, CDCl3) δ: 2.82-3.01 (m, 4H), 4.38 (d, J=5 Hz, 2H), 6.4 (m, 1H), 7.23-7.84 (m, 9H). Analysis calculated for C18H16N3OCl: C, 66.36; H, 4.95; N, 12.90. Experimental: C, 66.53; H, 5.23; N, 12.78.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35](Cl)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:35]([C:30]2[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=3)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:36])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a mixture of 4-aminophenylacetic acid ethyl ester (3.41 g), triethylamine (3.2 mL) and methylene chloride (30 mL) was added dropwise a solution of the 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride (5.40 g) obtained in Example 1-d) in methylene chloride (10 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. After addition of 1N hydrochloric acid, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and then concentrated to give the title compound (8.12 g).
Reaction SMILES: Cl.[F:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].O>C(Cl)Cl>[F:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH:5][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]
Reactant: CC(C)(F)CN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)CNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 48 h
Yield: 100.8 %

Procedure:
2-Fluoro-2-methylpropan-1-amine hydrochloride (4.02 g, 31.4 mmol) was dissolved in 80 mL of dry CH2Cl2. Triethylamine (13.1 mL, 94.2 mmol) and 4-chloro-3-nitro[1,5]naphthyridine (6.56 g, 31.4 mmol) were then added and the reaction was stirred under N2 for 2 days. The reaction mixture was then concentrated under reduced pressure to give a dark-yellow solid. The solid was treated with 200 mL of H2O and the mixture was heated to reflux with rapid stirring. The mixture was cooled and the yellow solid was isolated by filtration. The material was washed with H2O and the dried under vacuum to give N-(2-fluoro-2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (8.36 g) as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=O.N#N>C(N(CC)CC)C.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]1[O:10][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[N:13]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: N#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2F)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.17 h

Procedure:
5-Nitroanthranilic acid (0.6 g) was dissolved in triethyl amine/toluene (1/1) (18 mL) and stirred for 10 min. 2,6-Difluorobenzoylchloride (1.3 g) was slowly added under stirring which resulted in the formation of a precipitate. The reaction was performed in an N2-atmosphere. After stirring at RT for 24 h the mixture was extracted with sat.NaHCO3 and ethyl acetate (20 mL), the organic layer was separated and evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:35]=[CH:34][C:5]=1[CH2:6][N:7]([CH3:33])[C:8](=[O:32])[CH:9]=[CH:10][C:11]1[CH:31]=[N:30][C:14]2[NH:15][C:16](=[O:29])[CH2:17][N:18](CC3C=CC(OC)=CC=3)[CH2:19][C:13]=2[CH:12]=1)[CH3:2].[Cl:41]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:41].[CH2:1]([O:3][C:4]1[C:37]([CH:38]([CH3:39])[CH3:40])=[CH:36][CH:35]=[CH:34][C:5]=1[CH2:6][N:7]([CH3:33])[C:8](=[O:32])/[CH:9]=[CH:10]/[C:11]1[CH:31]=[N:30][C:14]2[NH:15][C:16](=[O:29])[CH2:17][NH:18][CH2:19][C:13]=2[CH:12]=1)[CH3:2]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCOc1c(CN(C)C(=O)C=Cc2cnc3c(c2)CN(Cc2ccc(OC)cc2)CC(=O)N3)cccc1C(C)C
Solvent: CC(Cl)Cl
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)cccc1C(C)C
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A suspension of N-(2-ethoxy-3-isopropylbenzyl)-3-[4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]-N-methylacrylamide (0.200 g, 0.369 mmol) in dichloroethane (8.0 mL) was cooled in an ice bath and treated with 1-chloroethyl chloroformate (0.044 mL, 0.40 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was heated to reflux for 2 h. The mixture was allowed to cool and then concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2 to CH2Cl2/MeOH, 100 to 99.5:0.5) gave a white solid (0.128 g, 0.241 mmol). The solid was dissolved in methanol (4 mL) and heated to reflux for 6.5 h. The mixture was allowed to cool and the resulting solid was isolated by filtration, washed with MeOH and Et2O and dried to give the title compound (1.28 g, 46%) as a white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 11.08-11.06 (m, 1H), 9.96 (br s, 2H), 8.77-8.71 (m, 1H), 8.32-8.23 (m, 1H), 7.63-7.55 (m, 1H), 7.40-7.32 (m, 1H), 7.26-7.21 (m, 1H), 7.13-7.04 (m, 1H), 6.91-6.84 (m, 1H), 4.83-4.67 (m, 2H), 4.27-4.22 (m, 2H), 3.88-3.78 (m, 4H), 3.29-2.25 (m, 1H), 3.13-2.89 (m, 3H), 1.40-1.35 (m, 3H), 1.19-1.17 (m, 6H); MS (ESI) m/e 423 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[I:13]I>C1COCC1.O>[CH2:1]([S:3]([C:6]1[N:11]=[C:10]([I:13])[C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:2].[CH2:1]([S:3]([C:6]1[N:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: II
Reactant: CCS(=O)(=O)c1ccc(O)cn1
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cc(I)c(O)cn1
Product: CCS(=O)(=O)c1ccc(O)c(I)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Step 4 (3 g, 16 mmol) in a mixture of THF (20 mL) and H2O (20 mL) was added KI (662 mg, 4 mmol) and iodine (6.1 g, 24 mmol). The reaction was stirred at rt for 1 hour and then heated to 60° C. for another 17 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove the THF. The mixture was diluted with water (100 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to afford 6-ethylsulfonyl-2-iodopyridin-3-ol and 6-ethylsulfonyl-4-iodopyridin-3-ol as white solids. 6-ethylsulfonyl-2-iodopyridin-3-ol: 1H NMR (DMSO-d6, 400 MHz) δ 7.85 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 3.30 (q, J=7.2 Hz, 2H), 1.11 (t, J=7.2 Hz 3H). LCMS: 313.8 (M+1)+; 6-ethylsulfonyl-4-iodopyridin-3-ol: 1H NMR (DMSO-d6, 400 MHz) δ 8.23 (s, 1H), 8.18 (s, 1H), 3.31 (q, J=7.2 Hz, 2H, overlapped with solvent peak), 1.10 (t, J=7.2 Hz 3H). LCMS: 313.8 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1.[CH3:22][O-:23].[Na+].O.Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:23][CH3:22])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1
Reactant: C[O-]
Reactant: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)cncc2Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cncc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Yield: 93 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)-pyrimidin-4-ol (see, e.g., Example 120; 1.0 g, 2.8 mmol) and a sodium methoxide solution (25% wt., 2.6 mL) in dimethyl sulfoxide (10 mL) was stirred at 70° C. overnight. Water (100 mL) was added, and the pH of the mixture was adjusted to around 6 with 2N HCl. The mixture was extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo to afford 2-{[(3-chloro-5-methoxypyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (912 mg. 93%); 1H NMR (500 MHz, DMSO-d6): δ 3.97 (s, 3H), 4.59 (s, 2H), 6.68 (s (br), 1H), 8.32 (s, 1H), 8.39 (s, 1H); M+ 352.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:32])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 80 °C

Procedure:
To a mixture of 7-benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one 3a (1.0 g, 4.14 mmol) and N,N-diethylaniline (0.37 g, 2.48 mmol) was slowly added POCl3 (12 mL). The mixture was heated to 80° C. for 20 h. After evaporation of the excess of POCl3, the residue was poured into ice, dichloromethane was added and the mixture was made basic (pH=11) with solid Na2CO3. The product was extracted with dichloromethane, dried, and concentrated. Flash column chromatography with 20% ethyl acetate:hexane gave 0.46 g of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 4a as a yellow oil.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]([B:11]1[O:19][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:12]1)=[CH2:10]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:7]([O:6][C:4]([CH:3]1[CH2:10][CH:9]1[B:11]1[O:19][C:16]([CH3:18])([CH3:17])[C:13]([CH3:14])([CH3:15])[O:12]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1B1OC(C)(C)C(C)(C)O1
Reaction time: 2 h
Yield: 104.6 %

Procedure:
Ethyl diazoacetate (3.49 g, 61.3 mmol) was added over 20 minutes to a stirred suspension of palladium (II) acetate (61 mmol) and vinylboronic acid pinacol ester (1.9 g, 12.26 mmol) in diethyl ether (30 mL) and stirred for 2 hours. The reaction was concentrated in vacuo and the residues distilled under vacuum (100-140° C. at 0.5-1 mbar) to afford 2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopropanecarboxylic acid ethyl ester (3.08 g, quant.) as a 4:6 mix of products, cis/trans isomers. 1H NMR 300 MHz (CHCl3-d): δ 4.26-4.25 (0.8 H, m), 4.12-4.12 (1.2 H, m), 1.83-1.82 (0.4 H, m), 1.76-1.75 (0.6 H, m), 1.28-1.27 (6 H, m), 1.26 (6 H, m), 1.22 (3 H, m), 1.16-1.05 (0.8 H, m), 1.01-1.00 (1.2 H, m), 0.58 (0.6 H, ddd, J=10.25, 7.44, 5.18 Hz), 0.41-0.41 (0.4 H, m)
Reaction SMILES: [O:1]1[C:5]2[C:6](C(O)=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N-:13]=[N+]=[N-].[Na+].[F:17][C:18]([F:23])([F:22])[C:19](O)=[O:20]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:17][C:18]([F:23])([F:22])[C:19]([NH:13][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)=[O:20]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(Nc1cccc2c1OCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
2,3-dihydrobenzofuran-7-carboxylic acid (D1) (1.42 g) was dissolved in a mixture of trifluoroacetic acid (50 ml) and trifluoroacetic anhydride (10 ml). After stirring at room temperature for 1.5 h, the mixture was cooled to 0° C. and treated portionwise with sodium azide (788 mg, 1.4 eq.), then stirred at room temperature for 2 days under argon. The mixture was evaporated under reduced pressure, and the residue partitioned between CHCl3 and water. The organic phase was washed with K2CO3 (aq), dried (Na2SO4) and the solvent evaporated under reduced pressure, to give the title compound (1.64 g, 82%) as an off-white crystalline material.
Reaction SMILES: [S:1]([NH:11][C@H:12]([C:20](O)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CN1CCOCC1.Cl.Cl.[NH:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][NH:34]/[C:33]/1=[N:42]\[C:43]([C:45]1[C:50]([NH2:51])=[N:49][C:48]([NH2:52])=[C:47]([Cl:53])[N:46]=1)=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:14]1([CH2:13][C@H:12]([NH:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])[C:20]([N:39]2[CH2:40][CH2:41][C:36]3([NH:32]/[C:33](=[N:42]/[C:43]([C:45]4[C:50]([NH2:51])=[N:49][C:48]([NH2:52])=[C:47]([Cl:53])[N:46]=4)=[O:44])/[NH:34][CH2:35]3)[CH2:37][CH2:38]2)=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of Tosyl-L-phenylalanine (1.0 g, 3.13 mmol) in DMF (25 ml) is added N-methyl morpholine (1.033 ml, 9.39 mmol) and 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (1.37 g, 3.44 mmol), followed by HATU (1.31 g, 3.44 mmol) and the resulting solution is stirred at room temperature for 20 minutes. The crude product is diluted with water (300 ml) and the resultant solid is isolated. Purification by reverse phase chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA) followed by catch and release resin (SCX-2) eluted with MeOH and 7M NH3 in MeOH yields a yellow solid which is triturated with MeOH and diethyl ether to give the title compound as a free base. The free base is stirred in 5M HCl at 100° C. for 30 minutes forming a gum. MeOH (5 ml) is added to the gum and then all solvent is removed in vacuo. The residue is triturated with MeOH and diethyl ether to give the title compound; [M+H]+ 626.4; 1H NMR (DMSO-d6): 1.12-1.71 (4H, m), 2.36-2.38 (3H, s), 2.59-2.83 (2H, m), 2.93-3.52 (4H, m), 3.41-3.60 (2H, m), 4.42 (1H, m), 7.12 (2H, d, J=6.9 Hz), 7.17-7.28 (3H, m), 7.35 (2H, d, J=7.7 Hz), 7.54-7.37 (2H, br), 7.57 (2H, d, J=7.7 Hz), 8.12 (1H, d, J=9.0 Hz), 7.70-8.26 (2H, br), 9.22 (1H, s), 9.95 (1H, s), 10.99 (1H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=[CH2:2].CO.[CH:13](OC=O)=O.C(O)=O.[NH2:21][NH2:22]>>[NH:21]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][N:7]=2)=[N:10][CH:13]=[N:22]1
Reactant: O=COC=O
Reactant: C=Cc1ccc(C#N)nc1
Reactant: NN
Solvent: CO
Solvent: O=CO
Product: C=Cc1ccc(-c2ncn[nH]2)nc1

Procedure:
5-vinylpicolinimidohydrazine (4-1) was synthesized by adding the 5-vinylpicolinonitrile intermediate (1-2) to a methanol solution, in which hydrazine was dissolved, and reacted at 24° C. 2-(1H-1,2,4-triazol-5-yl)-5-vinylpyridine (4-2) was prepared by reacting the 5-vinylpicolinimidohydrazine (4-1) with a mixed solution of formic anhydride and formic acid (in a volume ratio of 1:1).