Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>>[C:35]([C:37]1[CH:38]=[C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-cyano-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.88 (dd, J=6.60, 3.18 Hz, 6H), 1.47 (dt, J=13.45, 6.72 Hz, 1H), 1.66 (ddd, J=13.63, 7.09, 6.91 Hz, 1H), 1.91-2.00 (m, 1H), 3.77 (t, J=7.83 Hz, 1H), 7.61 (dd, J=4.16, 1.71 Hz, 2H), 7.68 (d, J=8.31 Hz, 2H), 7.73-7.81 (m, 7H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(Cl)Cl.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:22][N:23]=1
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1ccc(-c2cnnc(-c3ccccn3)n2)cc1-c1ccccn1
Temperature: 60 °C
Yield: 15.9 %

Procedure:
To a mixture of 5-(3-bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine (0.2 g, 0.67 mmol), cuprous 3-methylsalicylate (0.315 g, 1.5 mmol), 2-(tri-n-butylstannyl)pyridine (0.736 g, 2.2 mmol) and lithium chloride (0.085 g, 2.0 mmol) in dry 1,4-dioxane (8 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.032 mmol) and the mixture heated at 60° C. Fog 24 h. The reaction was allowed to cool to ambient temperature, diluted with DCM (20 ml) and washed with 10% ammonia solution (10 ml). The organic layer was washed with water (40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel, eluent 3% methanol in dichloromethane. The solid obtained was triturated with diethyl ether to give 5-[4-fluoro-3-(pyridin-2-yl)phenyl]-3-(pyridin-2-yl)-[1,2,4]triazine as a powdery orange solid (35 mg): δH (400 MHz, CDCl3) 7.39-7.48 (3H, m), 7.51 (1H, m), 7.81-8.00 (3H, m), 8.47 (1H, m), 8.71 (1H, m), 8.80 (1H, m), 8.93 (1H, m), 9.81 (1H, s); m/z (ES+) 330 (M++H).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=1)[CH3:6].N(CCO)CCO>ClCCl>[CH2:5]([S:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: CCSc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: OCCNCCO
Solvent: ClCCl
Product: CCSc1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
Boron tribromide (1M in dichloromethane, 70 ml, 70 mmol) was added dropwise to a solution of 1-(ethylsulfanyl)-3-methoxybenzene (5.9 g, 35 mmol) in dichloromethane (150 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 18 h then cooled to 0° C. A solution of diethanolamine (20 ml) in dichloromethane (40 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then poured onto ice water. The mixture was extracted with dichloromethane and the organic phase was washed with 2N hydrochloric acid, water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 30:70) as eluant to give 3-(ethylsulfanyl)phenol (4.53 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:11](=[O:22])C1C=CC(C(F)(F)F)=CC=1)=O.ClC1C=CSC=1C(NN)=O.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38](C(Cl)=O)=[CH:37][CH:36]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:22][CH2:11][N:10]([C:38]2[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:43][CH:42]=2)[N:9]=1
Reactant: O=C(NNC(=O)c1sccc1Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: NNC(=O)c1sccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(N2COC(c3sccc3Cl)=N2)cc1
Yield: 93 %

Procedure:
N-(3-Chloro-thiophene-2-carbonyl)-N′-(4-trifluoromethylbenzoyl)-hydrazine: A solution of 3-chloro-2-thiophenecarboxylic acid hydrazide (70.4 mg, 0.4 mmol), 4-trifluoromethylbenzoyl chloride (83.6 mg, 0.4 mmol) in pyridine (5 mL) was refluxed for 4 h and then cooled. The solution was diluted by water and the precipitate was collected by filtration, and then dried to yield 129 mg (93%) of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]>C1C=CC=CC=1>[CH3:1][O:2][CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]
Reactant: C[O-]
Reactant: CN(CCl)S(=O)(=O)Cl
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COCN(C)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 13.5 parts of sodium methylate in 110 parts of methanol is added, in the course of 15 minutes at from 0° to 5° C., to a mixture of 44.5 parts of N-chloromethyl-N-methylsulfamic acid chloride in 260 parts of benzene. The reaction mixture is then stirred for 2 hours at 25° C., after which the sodium chloride which has precipitated is filtered off. After removing the solvent under reduced pressure, distillation gives 29.1 parts (67% of theory) of N-methoxymethyl-N-methylsulfamic acid chloride of boiling point 84°-87° C./12 mbar and nD25 =1.4536.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(Cl)Cl.CCN(CC)CC>[CH2:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a stirred solution of 3-hydroxymethylpiperidine (1 g, 8.7 mmol) in CH2Cl2 (50 mL) and Et3N (1.12 mml) at 0° C. was added dropwise CbzCl (1.24 mL, 8.7 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography with hexane-EtOAc (2:1) to give a colorless oil (2 g, 94%). 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.12 (m, 2H), 4.20-3.60 (m, 2H), 3.47 (m, 2H), 3.20-2.20 (m, 3H), 1.82-1.10 (m, 5H); 13C NMR (CDCl3) δ 155.55, 136.73, 128.38, 127.85, 127.69, 66.96, 64.31, 46.74, 44.71, 38.01, 26.77, 24.05.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][NH2:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30]([C:33](=O)[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1>>[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30](/[C:33](=[N:11]/[NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])/[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1
Reactant: NNC(=O)Nc1ccccc1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\NC(=O)Nc1ccccc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 36 %

Procedure:
The title compound was prepared from N-phenylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 36% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 9.06 (s, 1H), 8.86 (dd, 1H), 8.30 (t, 2H), 8.06 (d, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.60 (d, 2H), 7.48 (q, 1H), 7.31 (t, 2H), 7.04 (t, 1H), 4.58 (s, 2H), 2.32 (s, 3H). LCMS (method C): [MH]+=454, tR=3.89 min.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Br[CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10](OC)=[O:11]>C1COCC1>[CH3:1][N:2]1[CH2:7][C:8]2[C:9](=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:10]1=[O:11]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of methylamine in ethanol (10 mL, 80 mmol, 8M solution in ethanol) was added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (Compound 17G, 8.1 g, 29.6 mmol) in THF (30 mL). After stirring for 2 h the reaction mixture was concentrated to dryness and water (30 mL) was added with rapid stirring. The solids produced were isolated by filtration and dried to give 4.35 g of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (yield: 78%). 1H NMR (CDCl3, 400 MHz): δ 3.21 (s, 3H), 4.44 (s, 2H), 7.64 (m, 2H), 7.73-7.74 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[H-].[Na+].[CH3:19]I.[ClH:21]>C1COCC1.CCO>[ClH:21].[CH3:19][O:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCC1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
N-Boc-4-(2-hydroxy-ethyl)-piperidine (5 g, 21.8 mmol) in THF (25 ml) was added to a suspension of NaH (1.47 g, 43.7 mmol) in THF (75 ml) at 0° C. under N2. The reaction was stirred for 1 hour at 0° C. and MeI (2.72 ml, 43.7 mmol) added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 ml) and extracted with DCM (3×100 ml). The combined DCM layers were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo. The crude reaction (7.5 g) was treated with 3M HCl solution in EtOH (150 ml) for 12 hours. The reaction was concentrated in vacuo and azeotroped with toluene (2×150 ml) to give 4-(2-methoxy-ethyl)-piperidine hydrochloride (3.5 g, 89%) as a pale yellow solid.
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[CH:31]=O)=[O:28])=[CH:20][C:19]=2[CH3:39])#[CH:14].C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)(=O)C>[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[C:31]#[CH:1])=[O:28])=[CH:20][C:19]=2[CH3:39])#[CH:14]
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(C=O)COC)cc2c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(C#C)COC)cc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
A mixture of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (Bestmann's reagent) (77 mg) and 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (110 mg) in MeOH (10 ml) was cooled to 0° C. Solid K2CO3 (71 mg) was added and the mixture stirred during 16 hour allowing the temperature raising to 25° C. The reaction mixture was diluted with ethyl acetate and poured onto brine. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography to give 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl-acetamide (60 mg) as a light brown solid as a mixture of diastereoisomers.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[SH:19][C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][S:19][C:20]2[NH:21][C:22]3[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[CH:25][C:23]=3[N:24]=2)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1ccc2nc(S)[nH]c2c1
Product: CCCc1c(OCC(O)CSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O

Procedure:
Ethyl 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio]benzimidazole-5-carboxylate was prepared in a similar manner to Example 2 with 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-1,2-epoxypropane (1.91 g) and ethyl 2-mercaptobenzimidazole-5-carboxylate (1.70 g). 2.10 g (58.1%) of the esters was obtained as a yellow oil. This ester (2.10 g) was converted to the title compound (870 mg. 44.1%) as pale brown crystals in the same manner as Example 2, mp 133-135° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](O)=O.P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[CH3:1][NH:2][C:3]1[S:6][C:10]([C:9]([CH3:14])([CH3:13])[CH2:8][Cl:7])=[N:5][N:4]=1
Reactant: CC(C)(CCl)C(=O)O
Reactant: CNC(=S)NN
Agent: Cl
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(C(C)(C)CCl)s1

Procedure:
To a well stirred suspension of 125 g of 4-methylthiosemicarbazide and 165 g of β-chloropivalic acid in 500 ml of dioxane was added 186 g of phosphorus oxychloride at a rate which maintained the temperature below 60°. The reaction mixture was then heated at reflux until HCl evolution ceased (about 4 hrs). After cooling, the supernatant liquid was decanted from the plastic mass and 500 ml of water was added. With cooling, sodium hydroxide pellets were added until a pH of 10 was maintained. The resulting precipitate was collected, washed with water and air dried giving 216 g m.p. 91°-93°, (87%). Recrystallization from methylene chloride-ether gave the analytical sample, m.p. 93°-95°.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=3)[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:26]O.C=O>C(Cl)Cl>[CH3:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8]3[N:9]([CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=3)[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][N:12]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCNCC3)c2n1
Reactant: CO
Agent: C=O
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCN(C)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A 25 mL round bottom flask was charged with ethyl 8-(piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,2-a]pyrazine-2-carboxylate (200 mg, 0.56 mmol), MeOH (15 mL), CH2Cl2 (15 mL), 40% aqueous formaldehyde (1 mL) and NaBH3(CN) (250 mg, 3.9 mmol). The mixture was stirred at 25° C. for 1 h. Reaction progress was monitored by LC-MS. Work-up: the solvent was evaporated. The residue was purified by flash column chromatography on silica gel with a 1:20 MeOH/CH2Cl2, to afford 150 mg (72%) of the product. 1H NMR (300 MHz, CDCl3) δ: 8.33 (s, 1H), 7.50 (s, 1H), 7.48 (dd, J=5.4, 1.2 Hz, 1H), 7.35 (dd, J=3.3, 1.2 Hz, 1H), 7.20 (dd, J=5.4, 3.3 Hz, 1H), 4.43-4.38 (m, 6H), 2.59 (t, J=5.1 Hz, 4H), 1.40 (t, J=6.9 Hz, 3H). MS m/z: 372 (M+H+).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]1=O)=[O:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[NH:20]>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([C:19]2[N:20]=[C:3]([OH:4])[C:5]3[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=3[N:21]=2)[CH:22]=1
Reactant: COC(=O)C1CC(C)(C)CC1=O
Reactant: N=C(N)c1cc(Cl)ccc1F
Solvent: CCO
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(O)c2C1
Yield: 58.8 %

Procedure:
A solution of 4,4-Dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester (2.08 g, 12.21 mmol) and 5-Chloro-2-fluoro-benzamidine (2.32 g, 13.44 mmol) in 100% ethanol (40 mL) was heated to reflux overnight, then cooled and evaporated. The residue was dissolved in 1N (aq.) NaOH (50 mL) and washed with methylene chloride (2×50 mL). The aqueous layer was then acidified with glacial acetic acid to pH4 and extracted with methylene chloride (2×100 mL). The organic extracts were dried (brine and MgSO4) and evaporated to give crude product, purified by chromatography (CH2Cl2, 0-10% MeOH) to give the desired product as a cream solid (2.10 g, 59% yield).
Reaction SMILES: C1(C#C)C=CC=CC=1.[CH:9]1([CH2:15][CH2:16][C:17]#[CH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:18]=[C:17]([CH2:16][CH2:15][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C#CCCC1CCCCC1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CCC3CCCCC3)nn2)sc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 4-cyclohexylbutyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 22% yield: mp 82-84° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.37-7.33 (m, 5H), 6.19 (br s, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.68 (s, 3H), 1.78-1.56 (m, 5H), 1.30-1.16 (m, 5H), 0.99-0.71 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.7, 153.3, 149.9, 137.5, 128.8, 127.8, 123.8, 118.2, 44.3, 37.0, 36.5, 33.1, 26.5, 26.2, 22.9, 17.4; MS (ES+) m/z 410.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH3:14]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: N
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(N)(=O)=O
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-methoxybenzene sulfonyl chloride (1.0 g, 4.15 mmol) in tetrahydrofuran (10 mL) was bubbled ammonia gas until saturated. The reaction was stirred overnight. The white solid that precipitated out of solution was collected by filtration and washed with dichloromethane to give the title compound (0.52 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C[O-].[Na+].O.[C:19](OCC)(=[O:21])C>O1CCCC1>[CH3:19][O:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C

Procedure:
1-Fluoro-4-nitro-2-trifluoromethylbenzene 67 (0.1 mol), was dissolved in tetrahydrofuran (100 mL). The solution was cooled to 0° C. and sodium methoxide (0.1 mol) was added. The reaction was warmed to room temperature over 2 hours. Water and ethyl acetate were added. The organic phase was dried and concentrated to afford 1-methoxy-4-nitro-2-trifluoromethylbenzene 68. This material was dissolved in methylene chloride (100 mL) and the solution was cooled to −78° C. Boron tribromide (0.1 mol) was added. The mixture was warmed to room temperature. Water was added, and the organic phase was dried and concentrated. Chromatography then afforded the title compound 69.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:28])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24](O)=[O:25])[NH:20][C:19]2=[O:27].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.N>CN(C)C=O>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:28])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24]([NH2:35])=[O:25])[NH:20][C:19]2=[O:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c(=O)c12
Yield: 0 %

Procedure:
A mixture of Example 40 (0.05 g, 0.105 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.048 g, 0.126 mmol), N-ethyl-N-isopropylpropan-2-amine (0.092 mL, 0.527 mmol) and 0.5 M ammonia (1.054 mL, 0.527 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. Purification by reverse phase chromatography (C18, CH3CN/10 mM ammonium acetate in water, 10-100% gradient) afforded the title compound (0.011 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 8.96-9.08 (m, 1H), 8.00 (d, J=2.37 Hz, 1H), 7.96-7.99 (m, 1H), 7.82 (dd, J=8.48, 2.37 Hz, 1H), 7.44-7.63 (m, 3H), 7.28 (s, 1H), 7.18-7.27 (m, 1H), 6.99 (d, J=7.46 Hz, 1H), 3.26 (s, 3H), 2.67 (s, 3H). MS (ESI+) m/z 474 [M+H]+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=CC=1)([O-])=O>>[N:51]1([C:48]2[CH:49]=[CH:50][C:45]([NH:44][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([N:26]6[CH2:27][CH2:28][O:29][CH2:30][CH2:31]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:5])=[CH:46][CH:47]=2)[CH2:52][CH2:53][CH2:54][CH2:55]1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1N1CCOCC1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCCC5)cc4)CC3)ncnc2cc1N1CCOCC1

Procedure:
The title compound was prepared from 4-(6-methoxy-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 211a, and (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 74a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 7.19 (m, 2H), 6.53 (m, 2H), 6.21 (s, 1H), 4.26 (m, 2H), 4.05 (s, 3H), 3.94 (m, 4H), 3.57 (tt, 1H), 3.31-3.24 (m, 8H), 3.15 (td, 2H), 2.20-2.08 (m, 2H), 2.03-1.94 (m, 6H). LC/MS (ESI): calcd mass 516.3, found 517.3 (MH)+.