Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][NH:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[CH:11]=2)=[C:6]([O:20][CH3:21])[N:5]=[C:4]([O:22][CH3:23])[N:3]=1.[CH3:24][C:25]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]1([C:12]2[CH:11]=[C:10]([NH:9][CH2:8][C:7]3[C:6]([O:20][CH3:21])=[N:5][C:4]([O:22][CH3:23])=[N:3][C:2]=3[CH:24]=[CH2:25])[N:14]([CH2:15][CH3:16])[N:13]=2)[CH2:19][CH2:18]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCn1nc(C2CC2)cc1NCc1c(Cl)nc(OC)nc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1nc(OC)nc(OC)c1CNc1cc(C2CC2)nn1CC

Procedure:
To a solution of N-((4-chloro-2,6-dimethoxypyrimidin-5-yl)methyl)-3-cyclopropyl-1-ethyl-1H-pyrazol-5-amine (2.42 g, 7.16 mmol) in DME (50 mL) and water (15 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.5 mL, 14.3 mmol), Pd(Ph3P)4 (0.828 g, 0.716 mmol) and sodium carbonate (2.47 g, 23.3 mmol). The mixture was sparged with argon for 15 min and then heated at reflux for 18 h. The mixture was then absorbed onto silica gel and dried under reduced pressure. After dry loading, the product was purified by FCC (10-75% EtOAc/heptane) to give 3-cyclopropyl-N-((2,4-dimethoxy-6-vinylpyrimidin-5-yl)methyl)-1-ethyl-1H-pyrazol-5-amine. MS (ESI+) m/z 330.1 (M+H)+.
Reaction SMILES: Cl[CH:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:5][CH:4]=[N:3]1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23].CCN(C(C)C)C(C)C>C(#N)C>[CH:22]([NH:26][CH:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:5][CH:4]=[N:3]1)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])C1C(c2ccc(OC(F)F)cc2Cl)=CC=NC1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(C)NC1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Temperature: 25 °C
Yield: 82.3 %

Procedure:
2-Chloro-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridine (0.176 g, 0.53 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of sec butylamine (106 μL, 1.06 mmol) and Hunig's base (184 μL, 1.06 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature, extracted with EtOAc/H2O, organic layer was then washed with 1N HCl and made basic with 1N NaOH. The organic layer was washed with brine, dried Na2SO4, filtered and concentrated to yield 0.163 g (83%) of sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine as a yellow oil; MS (AP) 413.0 [(M+H+CH3CN)+, 50].
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(OC(C)(C)C)=O)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@H:20]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:19]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@H:20]([O:29][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:33])[CH3:32])[CH2:19]2)[CH:4]=[C:5]([C:16]#[N:17])[CH:6]=1
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Yield: 79.3 %

Procedure:
Methyl ((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (242 mg, 0.354 mmol) was treated with TFA (25% in 1,2-dichloroethane, 4 mL, 12.98 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10), the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-20% ethyl acetate/dichloromethane). Methyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (135 mg) was obtained as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:7][C:8]#[N:9]>N1C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:7][C:8]#[N:9])=[CH:23][CH:22]=1
Reactant: COc1ccc(C(O)(CC#N)c2ccc(OC)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=CC#N)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Thionyl chloride (2.18 g, 0.018 mol) was slowly added to a stirred solution of 3-hydroxy-3,3-di(4-methoxyphenyl)propanenitrile (4.0 g, 0.014 mol) in pyridine (30 ml) cooled in an ice-salt bath. After the addition was complete the mixture was allowed to warm up to room temperature and stirred for 2 h. ice cold water (100 ml) was added and the mixture extracted with DCM (2×100 ml) The combined organics were washed with 3M hydrochloric acid (1×50 ml, 1×5 ml) , brine (50 ml) , dried over anhydrous sodium sulphate, filtered and evaporated to yield crude 3,3-di(4-methoxyphenyl)-2-propenenitrile (2.95 g, 79%) which was used directly in the next step.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25]C)=[O:24])[CH:18]=2)=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.C1COCC1>[CH3:5][C:3]([CH3:6])([O:7][C:8]([NH:10][C:11]1[S:12][C:13]([S:16][C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]([OH:25])=[O:24])=[CH:14][N:15]=1)=[O:9])[CH3:4]
Reactant: COC(=O)c1cccc(Sc2cnc(NC(=O)OC(C)(C)C)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncc(Sc2cccc(C(=O)O)c2)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1 N aqueous sodium hydroxide solution (50 mL, 50 mmol) was added dropwise to a stirred solution of 2-tert-butoxycarbonylamino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.8 g, (contaminated with bis(tert-butoxycarbonyl)amino adduct)) in a methanol-THF mixture (160 mL, 3:1). The solution was stirred at rt. for 24 h and concentrated. The residue was acidified with 2 N aqueous HCl (30 mL) and the suspension was extracted with dichloromethane-methanol mixture (120 mL, 3:1, 2×). The combined organic extract was dried (MgSO4), filtered and concentrated in vacuo to obtain the titled compound (1.32 g, 75% overall yield from Example 1, part A) as an off-white solid.
Reaction SMILES: Cl.[CH2:2]([CH2:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O>>[CH2:2]([CH2:9][NH:10][CH2:11][C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC1(c2cccnc2)CCCCC1CNCCc1ccccc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: c1ccc(CCNCC2=C(c3cccnc3)CCCC2)cc1
Yield: 26.5 %

Procedure:
5.5 g 2-[(benzylmethylamino)methyl]-1-pyridin-3-ylcyclohexanol hydrochloride and 27.5 ml thionyl chloride were heated at a bath temperature of 75° C. for one hour. After the mixture had been concentrated in vacuo, the residue was taken up in ethyl acetate and sodium hydroxide solution (32 percent strength by weight) and the organic phase was separated off, dried and concentrated. The crude product obtained (3.7 g) was chromatographed on silica gel with diisopropyl ether/ethyl acetate (V/V=2:1). 1.23 g benzylmethyl-(2-pyridin-3-ylcyclohex-1-enylmethyl)amine were obtained, and were dissolved in approx. 25 ml acetone and converted into the corresponding hydrochloride with 1.66 μl water and 1.18 ml chlorotrimethylsilane.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.Br[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>O>[CH2:25]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:24][CH2:23][CH:22]=[CH2:21]
Reactant: C1CC2(CCN1)OCCO2
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C=CCCCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a mixture of 15 g (0.105 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol) of K2CO3, and 100 ml of acetonitrile is added dropwise 14.41 ml (0.105 mol) of 5-bromopentene. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to furnish 18.62 g (84%) of title compound as an oil: IR (neat) 2940 and 1090 cm-1 ; NMR (CDCl3) δ5.84 (m, 1H), 5.02 (m, 2H), 3.96 (s, 4H), 2.70-1.40 (m, 14H).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](O)=[O:32])[CH:20]=[C:19]1[CH:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:41]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:21]([C:31](=[O:32])[NH2:41])[CH:20]=[C:19]1[CH:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 39, 0.65 g, 1.24 mmol) following the procedure described for Intermediate 20. The desired product was obtained as an off-white solid (0.322 g, 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:24][O:25]C1C=CC(NN)=CC=1>>[CH3:24][O:25][C:20]1[CH:21]=[CH:22][C:17]([N:15]2[C:14](=[O:23])[C:8]3=[CH:9][NH:10][C:11]4[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:7]3=[N:16]2)=[CH:18][CH:19]=1
Reactant: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Reactant: COc1ccc(NN)cc1
Product: COc1ccc(-n2nc3c4cc([N+](=O)[O-])ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 5a using 4-methoxy phenylhydrazine instead of phenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 3.77 (3H, s), 6.89 (1H, dd, J=8.91, 2.37 Hz), 6.95 (2H, m), 7.25 (1H, d, J=2.08 Hz), 7.44 (1H, d, J=8.91 Hz), 8.05 (2H, m), 8.39 (1H, d, J=6.53 Hz). m/z 337.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[CH:23][C:22](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(O)C.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[CH:23][C:22](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 62 was suspended in a mixed solution of ethanol (10 ml) and methylene chloride (10 ml), and 1N aqueous solution of sodium hydroxide (1 ml) was added to the suspension. The mixture was stirred at room temperature for 10 minutes, and the solvent was evaporated under reduced pressure. To the residue was added water and 1N hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration to obtain the title compound (160 mg, 84%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:23]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CC(C)c1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 31.8 %

Procedure:
5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazin-3-amine (110 mg, 33%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.3 g, 1.19 mmol) and 3-isopropyl phenyl boronic acid (0.215 g, 1.31 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][OH:48]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][OH:48])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCCCCCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCCCCO

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 6-amino-1-hexanol (34 mg) according to Method A to give the title compound (64 mg). 1H-NMR (400 MHz, CD3OD) d 7.79 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27-7.18 (m, 5H), 7.02 (dd, J=7.0 Hz, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.57 (m, 1H), 4.25 (dd, J=4.8 Hz, J=9.5 Hz, 1H), 3.77 (m, 1H), 2.74 (dd, J=10.2 Hz, J=13.2 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3291, 2932, 1691, 1647 cm−1; HRMS m/z 629.2948 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.ClC(Cl)(Cl)[C:34]([N:36]=C=O)=[O:35]>N1C=CC=CC=1>[C:34]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([CH3:31])=[CH:4]4)=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23])(=[O:35])[NH2:36]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(N)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (60 mg, 0.14 mmol), (prepared as described for the starting material in Example 12), was dissolved in pyridine (3 ml) and cooled to 0° C. Trichloroacetyl isocyanate (17 μl, 0.14 mmol) was added and the mixture stirred for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at ambient temperature overnight and then at 50° C. for 2 hours. The solvent was removed under reduced pressure. Column chromatography of the residue (2% to 5% methanol/dichloromethane) gave 7-[(2S)-1-carbamoylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (40 mg, 69%) as a yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([NH:36][CH2:35][CH2:33][OH:34])=[O:27])[C:8]2=[O:31])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Reactant: NCCO
Product: O=C(Cn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21)NC1CC1

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.25 (1H, t, J=5 Hz), 8.54 (1H, s), 8.25 (1H, d, J=4 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.5, 5.7 Hz), 7.11 (2H, t, J˜9 Hz), 4.92 (1H, br m), 4.80 (2H, s), 4.11 (2H, s), 3.54 (2H, t, J=5 Hz), 3.42 (2H, q, J˜5 Hz), 2.57 (1H, m), 0.59 (2H, m), 0.35 (2H, m); HRMS calcd for C23H23FN4O5+H+: 455.1731. Found: 455.1728.
Reaction SMILES: [CH2:1]1[S:5](=[O:7])(=[O:6])[O:4][CH2:3][CH2:2]1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>CO>[CH2:8]([NH:12][CH2:3][CH2:2][CH2:1][S:5]([OH:4])(=[O:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: O=S1(=O)CCCO1
Reactant: CCCCN
Solvent: CO
Product: CCCCNCCCS(=O)(=O)O
Reaction time: 0.67 h
Yield: 96 %

Procedure:
Propanesultone (61g; 0.5 mole) was added to a stirred solution of n-butylamine (36.5g; 0.5 mole) in methanol (200 ml) in 10 min. The reaction temperature was kept at 50°-55° by cooling. After stirring 40 min, a white solid began to separate. After stirring overnight filtration yielded 3-butylaminopropylsulfonic acid 94g (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]([CH3:17])[C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:20]O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:18][N:20]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]=2[CH3:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Yield: 3.6 %

Procedure:
The lithium enolate of ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (1.5 g, 5.5 mmol) and hydroxylamine hydrochloride (0.46 g, 6.6 mmol) in absolute ethanol (30 mL) were heated to reflux for 17 hours, cooled to room temperature, then cooled to 0° C. for 3 hours. The resulting white crystals were collected and dried under vacuum to obtain ethyl 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylate (0.55 g, 0.20 mmol).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: O=C1CCCO1
Product: CCCCNC(=O)CCCO
Temperature: 85 °C

Procedure:
To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 85° C. for 1.5 hr, then the excess n-butylamine was removed in vacuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][NH:11][C:10](Cl)([NH2:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1.C(N(CC)CC)C>C(#N)C.[OH-].[Na+]>[CH2:1]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][NH:11][C:10]([N:19]2[CH:23]=[N:22][N:21]=[N:20]2)([NH2:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nnn[nH]1
Reactant: NC1(Cl)N=C(Cc2ccccc2)C([N+](=O)[O-])=CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC1(n2cnnn2)N=C(Cc2ccccc2)C([N+](=O)[O-])=CN1
Reaction time: 8 h

Procedure:
4.0 g of 4N-benzyl-2-chloro-5-nitropyrimidineamine (Reference Example 2) is added to a solution of 3.0 g of 1H-tetrazol in 120 ml of acetonitrile. A mixture of 2.5 ml of triethylamine and 45 ml of acetonitrile is added dropwise to the solution. The reaction solution is stirred overnight and is concentrated under reduced pressure to obtain solid. The resulting solid is suspended in 3N sodium hydroxide solution for 1 hour, filtered and dried to obtain 3.80 g of the title compound.
Reaction SMILES: [ClH:1].O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[ClH:1].[CH2:4]1[C:5]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][C:6]=2[CH2:7][CH2:8][NH:3]1
Reactant: NNc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CCNC3
Yield: 87.6 %

Procedure:
4-Piperidone monohydrate hydrochloride (10 g, 65.1 mmol) and phenylhydrazine hydrochloride (9.4 g, 65.1 mmol) are suspended in ethanol (200 ml) and stirred at reflux overnight. The resulting solid is filtered off and washed with diethyl ether to afford pure sub-title compound (11.9 g) in 88% yield. tR (LC-2) 0.89; ESI-MS (positive ion): m/z 173.34 [M+H]+ (calcd 172.23 for C11H12N2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)=[O:10].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:36][CH2:37][CH2:38]I)[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH2:16][N:15]([CH2:38][CH2:37][CH2:36][N:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:14][CH:13]2[CH2:12]1)=[O:10]
Reactant: Cc1cccc(C)c1C(=O)N1CC2CNCC2C1
Reactant: O=S(=O)(c1ccccc1)N(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cccc(C)c1C(=O)N1CC2CN(CCCN(c3ccc(F)cc3)S(=O)(=O)c3ccccc3)CC2C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 66 (0.012 g, 0.05 mmol) in MeCN (1 mL) at RT were added N-(4-fluoro-phenyl)-N-(3-iodo-propyl)-benzenesulfonamide (102, 0.025 g, 0.06 mmol) and K2CO3 (0.01 g, 0.075 mmol). The reaction mixture was shaken at 80° C. for 48 h. After cooling to RT, the mixture was diluted with DCM (5 mL), filtered and evaporated in vacuo. The crude product was purified by reverse phase HPLC to afford II-2: MS (ES+) m/z=536 (M+H)+.