Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]2[N:10]=[C:9]([C:11]3[N:12]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:13]=[C:14]([Br:16])[CH:15]=3)[O:8][C:7](=[O:24])[C:6]=2[CH:25]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:16][C:14]1[CH:15]=[C:11]([C:9]([NH:10][C:5]2[C:4]([Br:26])=[CH:3][C:2]([Br:1])=[CH:25][C:6]=2[C:7]([NH:28][NH2:29])=[O:24])=[O:8])[N:12]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:13]=1
Reactant: NN
Reactant: O=c1oc(-c2cc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Under ice-cooling, 0.569 g of 6,8-dibromo-2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one, 0.20 g of hydrazine monohydrate and 2 ml of tetrahydrofuran were mixed, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 0.53 g of 4-bromo-N-[4,6-dibromo-2-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:8][CH:9]=[CH:10][N:11]=2)[CH2:3]1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[N:2]1[CH2:5][CH:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:8][CH:9]=[CH:10][N:11]=2)[CH2:3]1
Reactant: Oc1ccccc1-c1nccnc1C1CNC1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccccc1-c1nccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a solution of 2-(3-azetidin-3-yl-pyrazin-2-yl)-phenol hydrochloride (275 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1 mmol) in DMF (10 mL) was added Cs2CO3 (650 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×2). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 2-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol (56 mg, 0.16 mmol, yield 16%).
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[C:17]([CH2:20][OH:21])[S:18][CH:19]=1>CN(C=O)C>[OH:21][CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([NH:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])[N:16]=1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1csc(CO)n1
Solvent: CN(C)C=O
Product: CNC(=C[N+](=O)[O-])NCCSCc1csc(CO)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
14.11 g of 2-methylamino-2-methylthio-1-nitroethylene was added to a solution of 15.81 g of 4-[[(2-aminoethyl)thio]-methyl]-2-hydroxymethylthiazole in 190 ml of DMF. The solution was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure to give a residue which was chromatographed on silica gel eluting with 5-10% methanol in acetonitrile to give 12.8 g (61%) of N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine.
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=1[C:11](OC)=O>O1CCCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:9]([NH2:8])=[C:10]([C:11]2[O:7][N:6]=[C:3]([CH3:4])[N:5]=2)[CH:15]=1
Reactant: CC(N)=NO
Reactant: COC(=O)c1cc(OC)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N)c(-c2nc(C)no2)c1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
Sodium hydride (594 mg) was added to a stirred suspension of acetamide oxime (1.0 g) and 4 molecular sieves (4 g) in dry tetrahydrofuran (50 ml) under nitrogen. The mixture was heated at 60° for 30 min then allowed to cool to room temperature. A solution of 2-amino-5-methoxybenzoic acid, methyl ester (2.0 g) in dry tetrahydrofuran (20 ml) was added and the mixture stirred at reflux for 2.5 h. The suspension was allowed to cool, filtered and the filtrate evaporated to give the title compound as a yellow solid (1.64 g)
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:19]([N:8]([CH2:7][C:6]([OH:27])=[O:5])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
An ice-cooled solution of [octyl-(toluene-4-sulfonyl)amino]-acetic acid tert-butyl ester (5.2 g, 0.013 mol) in dichloromethane (50 ml) was further diluted by the addition of 25% TFA in dichloromethane (200 ml). The reaction mixture was stored at 4° C. overnight. Solvents were removed under reduced pressure and the residue was azeotroped with toluene. The resulting crude oil was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title compound as a white solid (4.4 g, 99%). 1H NMR: δ(CDCl3), 9.77 (1H, br s), 7.71 2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.2 Hz), 4.00 (2H, br s), 3.19 (2H, dd, J=7.4, 7.7 Hz), 2.38 (3H, s), 1.50-1.30 (2H, m), 1.30-1.05 (10H, m) and 0.85 (3H, t, J=6.6 Hz).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH2:11])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19](=S)=[S:20]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:19](=[S:20])[NH:11][CH:10]=2)[CH:9]=1
Reactant: NCc1ccc(F)cn1
Reactant: S=C=S
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1ccc2c[nH]c(=S)n2c1
Temperature: 75 °C
Yield: 33.5 %

Procedure:
In a round-bottomed flask, (5-fluoropyridin-2-yl)methylamine dihydrochloride (600 mg, 3.0 mmol) was suspended in methanol (16 ml). Triethylamine (1.4 ml, 10.0 mmol) was added followed by carbon disulfide (1.4 ml, 23.2 mmol). The reaction mixture was stirred at reflux (oil bath temperature=75° C.) overnight then cooled to room temperature and then concentrated. The residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane then the organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 169 mg (33%) of 6-fluoro-2H-imidazo[1,5-a]pyridine-3-thione as an orange solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.47 (br. s., 1H), 8.04 (dd, J=4.9, 1.1 Hz, 1H), 7.43-7.56 (m, 2H), 6.88 (ddd, J=10.0, 7.9, 2.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:39]>>[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41]1)[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-ethylpiperazine according to conditions described in general procedure C. Mp: 86-87° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.96 (s, 3 H), 1.58-1.59 (m, 6 H), 2.26 (bs, 4 H), 3.26-3.31 (m, 8H), 3.46 (bs, 2 H), 6.21 (d, J=5.8 Hz, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1 H), 7.45 (s, 1 H), 7.55-7.61 (m, 3 H), 7.81-7.83 (m, 1 H), 7.97 (d, J=7.7 Hz, 1 H), 8.25 (d, J=5.5 Hz, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)Nc2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a cooled (−78° C.) solution of 6-chloro-1,3-dihydro-indol-2-one (4.0 g, 24 mmol) and TMEDA (11.2 mL, 79 mmol) in THF (100 mL) was slowly added BuLi (2.2 M solution in cyclohexane, 22 mL, 48 mmol). The solution was stirred for 30 minutes at the same temperature and then iodomethane (2.2 mL, 36 mmol) was slowly added. The reaction was stirred at −20° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Chromatography (SiO2, EtOAc/Petrol 2:8) gave the title compound (2.7 g) as a pale pink solid. MS: [M+H]+=182.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:50]=[CH:49][C:11]([C:12]([O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:47]=[C:45]([CH3:46])[C:43](=[O:44])[NH:42][C:40]3=[O:41])[CH2:36][C@@H:35]2[OH:48])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].C(N(C(C)C)CC)(C)C.C(CC[O:64][P:65](Cl)[N:66](C(C)C)C(C)C)#N>ClCCl>[P:65]([O:48][C@@H:35]1[C@@H:34]([CH2:33][O:32][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:11]2[CH:49]=[CH:50][C:8]([O:7][CH2:1][CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6])=[CH:9][CH:10]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:17][CH:18]=2)[O:38][C@@H:37]([N:39]2[CH:47]=[C:45]([CH3:46])[C:43](=[O:44])[NH:42][C:40]2=[O:41])[CH2:36]1)([NH2:66])[OH:64]
Reactant: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OP(N)O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Compound 31 (3.0 grams, 4.43 mmol) was dissolved in anhydrous dichloromethane and diisopropylethylamine (2.7 mL; 15.5 mmol) was added. The solution was cooled to 0° C. and 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (2.0 mL, 8.86 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring under argon. After 4 hours the solution was diluted with dichloromethane and washed with a 5% aqueous solution of sodium bicarbonate (2×). The organic phase was dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel; EtOAc/hexane, 3/7) to afford 2.8 grams (72%) of compound 32 as a fluffy white solid. 1H NMR (300 MHz, CDCl3) δ 1.01-1.20 (m, 12H), 1.41 (s, 3H), 2.25-2.67 (m, 8H), 3.26-4.22 (m, 11H), 4.60-4.65 (m, 1H), 5.02 (dd, J=1.5, 10.4 Hz, 2H), 5.14 (dd, J=1.5, 17.3 Hz, 2H), 5.69-5.84 (m, 2H), 6.11-6.48 (m, 5H), 6.82 (dd, J=3.2, 8.9 Hz, 4H), 7.16-7.43 (m, 9H), 7.62 (d, J=15.2 Hz, 1H), 8.05 (bs, 1H); 31P NMR (300 MHz, DMSO-d6) 152.9, 152.4; Anal. Calcd for C50H61N4O8P1 (877.0276): C, 68.48; H, 7.01; N, 6.39. Found: C, 68.48; H, 7.22; N, 6.33. ##STR18##
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccccc2CO)cc1
Yield: 84.4 %

Procedure:
Prepared as in Example 46, using 2.0 g (5.8 mmol) of the material from Example 47 and 0.22 g (5.8 mmol) of sodium borohydride in 5 mL of ethanol. Afforded 1.7 g (84%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nccc(C#Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
Into a 250 mL round-bottomed flask was charged 1-(benzyloxy)-4-ethynylbenzene (2.0540 g, 9.86 mmol) and tetrahydrofuran (49.3 ml). 2,4-Dichloropyrimidine (1.469 g, 9.86 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.346 g, 0.493 mmol), copper(I) iodide (0.033 ml, 0.986 mmol), and triethylamine (4.12 ml, 29.6 mmol) were added. The reaction was heated to 45° C. overnight. Silica gel (approx. 15 g) was added, and the reaction concentrated. The reaction was purified by flash chromatography (10% ethyl acetate:hexanes for 10 minutes, then to 30% ethyl acetate:hexanes over 30 minutes, then to 50% ethyl acetate in hexanes over 5 minutes, then to 100% ethyl acetate over 5 minutes.) to provide the title compound. MS (ESI) m/e 321 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH:25]([F:27])[F:26])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[N:30]=[CH:29]1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([O:24][CH:25]([F:27])[F:26])[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:34](=[O:35])[CH2:33][C:31]1[NH:30][CH:29]=[N:28][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Reactant: O=C(O)Cc1c[nH]cn1
Product: O=C(Cc1cnc[nH]1)N1CCN(c2ccc(OC(F)F)c(OC(F)F)c2)C[C@@H]1Cc1ccccc1
Yield: 45 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3,4-bis-difluoromethoxy-phenyl)-piperazine and (1H-imidazol-4-yl)-acetic acid to afford the title compound as colorless solid (55 mg, 45%). LC/MS (Method B) 2.72 min, [M+1]+ 493.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45])=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCO
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCCCO)cc2)cc1

Procedure:
The product from Example 104A and 4-amino-1-butanol were processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ8.95 (s, 1 H), 7.74 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.86 (m, 4 H), 4.03 (d, 4 H), 3.35 (m, 2 H), 3.03 (m, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.34 (m, 2 H), 1.37 (m, 4 H); MS (ESI+) m/z 616 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:31]2=[O:32])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 7-(pyridin-4-yl)heptanoate (2.0 eq., prepared in Synthetic Example 15) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[5-(pyridin-4-yl)pentyl]-1,8-naphthyridin-2(1H)-one, mp 188.8 to 189.6° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: C([NH:6][C:7]1[NH:8][C:9](=[O:27])[C:10]2[N:11]=[CH:12][N:13]([C@@H:16]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@@:17]3([C:25]#[CH:26])[F:24])[C:14]=2[N:15]=1)(=O)C(C)C>N.C(OCC)(=O)C>[C:25]([C@@:17]1([F:24])[C@H:18]([OH:19])[C@@H:20]([CH2:22][OH:23])[O:21][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:9](=[O:27])[NH:8][C:7]([NH2:6])=[N:15][C:14]1=2)#[CH:26]
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Agent: N
Solvent: CCOC(C)=O
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.6 %

Procedure:
6b (1.33 mmol) was dissolved in saturated methanolic ammonia (62 mL) and stirred at room temperature for 20 h. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified on reverse phase column chromatography (C 18) eluting with a gradient 2-15% of acetonitrile in water. The residue obtained was then dissolved in hot ethyl acetate, filtered and dried to give the title compound (134 mg, 33%). Yellow solid. Molecular Formula C12H12FN5O4 1H NMR (DMSO-d6, 400 MHz) δ(ppm) 10.70 (ls, 1H, NH), 7.98 (s, 1H, H-8), 6.60 (ls, 2H, NH2), 6.21 (d, 1H, OH-3′, JOH-3′=7.6 Hz), 5.83 (d, 1H, H-1′, J1′-F=16.9 Hz), 5.29 (t, 1H, OH-5′, JOH-5′=5.2 Hz), 4.50 (td, 1H, H-3′, J3′-F=22.8 Hz, J3′-4′=9.2 Hz), 3.93-3.81 (m, 3H, H-4′, H-5′ and ethynyl), 3.70 (m, 1H, H-5″). 13C NMR (DMSO-d6, 100 MHz) δ(ppm) 157.2 (C-6), 154.3 (C-2), 151.05 (C-4), 135.1 (C-8), 116.7 (C-5), 96.4 (d, C-2′, 1JC-F=182.1 Hz), 87.4 (d, C-1′, 2JC-F=39.2 Hz), 83.1 (d, CCH, JC-F=9.1 Hz), 82.4 (C-4′), 76.2 (d, CCH, 2JC-F=31.2 Hz), 73.2 (d, C-3′, 2JC-F=20.1 Hz), 59.5 (C-5′). 19F NMR (DMSO-d6, 235 MHz) δ(ppm) −158.5 (m). LC/MS (A): (M+H+) 310.1 (5.55 min). LRFAB-MS (GT): 619 (2M-41)+, 310 (M+H)+, 152 (B+H)+, 617 (2M−H)−, 308 (M−H)−. UV λmax 253 nm
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)(=O)=O.[CH3:26][S-:27].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:14][C:10]1([CH3:13])[O:9][C@H:8]([C@@H:7]([NH:15][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:6][S:27][CH3:26])[CH2:12][O:11]1
Reactant: C[S-]
Reactant: CC1(C)OC[C@@H]([C@H](COS(C)(=O)=O)NC(=O)OCc2ccccc2)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSC[C@H](NC(=O)OCc1ccccc1)[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of the product from Example 27.2 (2.58 g, 6.91 mmol) in dimethylformamide (10 ml) was added sodium thiomethoxide (0.630 g, 8.98 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water (4×), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (ethyl acetate-petrol, 1:4) giving a colourless oil (2.007 g, 89%). 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.12 (ABq, 2H), 5.07 (br. s, 1H), 4.47 (bit, J=7.2 Hz, 1H), 4.05 (t, J=7.2 Hz, 1H), 3.83 (brq, J=7.2 Hz, 1H), 3.70 (dd, J=8.3, 6.8 Hz, 1H), 2.69 (d, J=7.6 Hz, 2H), 2.15 (s, 3H), 1.42 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.[Br:26][C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[N:32][C:31]=2Cl.C([O-])(O)=O.[Na+]>C(O)(C)(C)C.Cl.O1CCOCC1>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:31]3[N:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[N:29]=[CH:28][C:27]([Br:26])=[CH:36]4)[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:15])[F:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Reactant: Clc1nccc2cc(Br)cnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: NC1=N[C@@](c2cc(Nc3nccc4cc(Br)cnc34)ccc2F)(C(F)F)COC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
[(R)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]carbamic acid tert-butyl ester (CAS registry 1262859-09-5) (250 mg, 0.696 mmol) and 3-bromo-8-chloro-[1,7]naphthyridine [Heteroaryl 1] (186 mg, 0.765 mmol) were dissolved in tert-Butanol (4 ml) in a microwave vial and HCl (0.174 ml of a 4M solution in dioxane) was added. The vial was sealed and heated to 100° C. for 1 h. The reaction mixture was cooled to rt and added to a saturated NaHCO3 solution (20 ml) and stirred at rt for 10 min.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C=[CH:48][N:47]=[CH:46][C:45]=1CCl>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[N:47][CH:46]=[CH:45][C:44]=3[Cl:43])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: ClCc1cnccc1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cnccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-chloro-3-(chloromethyl)pyridine and isolated as light yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][OH:7])[CH2:4][CH3:5])[CH3:2].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:17])[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[OH:7])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CCC(CC)NO
Product: CCC(CC)N(O)C(=O)Nc1ccc(Br)cc1

Procedure:
Using the method of Compound 39 Part C, N-(1-ethylpropyl)hydroxylamine (2.6 g, 25 mmol) was reacted with 4-bromophenyl isocyanate (5 g, 25 mmol) to provide 2.1 g of the desired product as a solid, m.p. 129°-131° C. Analysis: Calculated for C12H17BrN2O2 : %C, 47.86; %H, 5.69; %N, 9.3; Found: %C, 47.79; %H, 5.54; %N, 9.25.