Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].C1CCN2C(=NCCC2)CC1.[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52]([CH:53]=O)=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52](/[CH:53]=[C:5](\[O:4][CH2:2][CH3:3])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(=C/c1cc(F)c(OCc2ccccc2)c(F)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (1,2-diethoxy-2-oxoethyl)triphenylphosphonium chloride (679) (1.61 g, 3.76 mmol) in tetrahydrofuran (56 mL) was added DBU (0.67 ml, 4.51 mmol) and the reaction was stirred for 10 minutes at room temperature. 4-(benzyloxy)-3,5-difluorobenzaldehyde (1.40 g, 5.64 mmol) was added in one portion and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo, diethyl ether was added and the solids filtered. The filtrate was concentrated in vacuo and the residue oil was purified by flash column chromatography (0-30% EtOAc in hexanes) to provide (Z)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-ethoxyacrylate (680).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](Cl)=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[N:15][N:14]2[CH:23]=1.Cl.[NH2:25][C@@H:26]([C@H:28]([C:31]1[O:32][CH:33]=[C:34]([C:36]([NH2:38])=[O:37])[N:35]=1)[CH2:29][CH3:30])[CH3:27]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([NH:25][C@@H:26]([C@H:28]([C:31]3[O:32][CH:33]=[C:34]([C:36]([NH2:38])=[O:37])[N:35]=3)[CH2:29][CH3:30])[CH3:27])=[C:17]([C:20](=[O:21])[NH2:22])[CH:16]=[N:15][N:14]2[CH:23]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 90 °C
Yield: 93.7 %

Procedure:
DIPEA (1.08 ml, 6.21 mmol) was added in one portion to a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (568 mg, 2.07 mmol) and 2-((2R,3R)-2-aminopentan-3-yl)oxazole-4-carboxamide hydrochloride (532 mg, 2.28 mmol) in DMF (6.9 ml). The reaction was heated to 90° C. overnight before evaporating in vacuo and treating the residue with water to precipitate 2-((2R,3R)-2-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)pentan-3-yl)oxazole-4-carboxamide (843 mg, 1.94 mmol, 94% yield) which was used immediately in the next reaction. 1H NMR (400 MHz, CCl3D) δ 8.00 (s, 1H), 7.81 (s, 1H), 7.34 (d, J=1.5 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 4.51-4.37 (m, 1H), 2.90 (dt, J=9.6, 4.9 Hz, 1H), 1.78-1.53 (m, 2H), 1.08 (d, J=6.4 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H). LC/MS: M+H+337.08, ret. time=0.84 min. Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[CH:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:9]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1ncc(-c2ccccc2Cl)n1
Product: Clc1ccccc1-c1cnn(CCC#Cc2ccccn2)n1
Yield: 45.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole (200 mg, 0.86 mmol) and 2-bromopyridine (150 mg, 0.95 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 120 mg (0.39 mmol, 45%) of 2-(4-(4-(2-chlorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a brown oil.
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1.[CH3:12][C:13]1[N:14]=[C:15]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH:8]1([CH2:7][N:25]2[CH2:26][CH2:27][N:23]([C:15]3[S:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:12])[N:14]=3)[C:24]2=[O:28])[CH2:11][CH2:10][CH2:9]1
Reactant: BrCC1CCC1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCC3)C2=O)nc1C
Yield: 88 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl)cyclobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 88% yield: 1NMR (300 MHZ, CDCl3) δ 4.29-3.96 (m, 4H), 3.60-3.23 (m, 4H), 2.63-2.48 (m, 4H), 2.09-2.02 (m, 2H), 1.93-1.83 (m, 2H), 1.77-1.68 (m, 2H), 1.26 (t, J=7.3 Hz, 3H); MS (ES+) m/z 324.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:28])[C:13]([S:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]2)(=[O:18])=[O:17])([CH3:15])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH3:4].[C:29]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[C:29]([Si:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[O:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:28])[C:13]([S:16]([CH2:19][CH:20]2[CH2:21][CH2:22][CH:23]([O:26][CH3:27])[CH2:24][CH2:25]2)(=[O:18])=[O:17])([CH3:15])[CH3:14])[O:8][N:7]=1)([CH3:4])[CH3:5])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)CO)no2)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)no2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 116.1 %

Procedure:
To a solution of 0.41 g (0.96 mmol) of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide in DCM (8 ml) are added imidazoles (0.07 g, 0.96 mmol), followed by tert-Butylchlorodiphenylsilane (0.26 g, 0.96 mmol). The reaction is stirred at room temperature for 20 h. The mixture is diluted with DCM (10 mL) and washed with saturated aqueous NH4Cl solution, brine, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure to give 0.73 g of N-{3-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide. Yield: 100%, ES-MS: 655 [M+H].
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[CH:12][C:4]=2[CH:3]=1.[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:23][CH2:22]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=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:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:27]=[C:28]([F:42])[C:29]([CH3:41])=[C:30]([C:2]3[C:7](=[O:8])[N:6]([CH3:9])[C:5]4[N:10]([C:13]5[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=5[F:20])[N:11]=[CH:12][C:4]=4[CH:3]=3)[CH:31]=2)[CH2:22][CH2:23]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 130 °C
Yield: 66.3 %

Procedure:
A mixture of 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (110 mg, 0.32 mmol), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (122 mg, 0.38 mmol) and 15 mg of Pd(PPh3)4 in 2.0 mL dioxane and 0.8 mL of 1 M Na2CO3 in a sealed glass tube was heated at 130° C. for 30 min. The reaction mixture was diluted in EtOAc, washed with 1 N NaOH solution. The organic phase was dried over MgSO4, filtered and concentrated. Purification of the brown residue on an ISCO 12 g column (40-80% EtOAc in Hexanes) afforded the title compound (96 mg) as an off white amorphous solid. MS (ESI, pos.ion) m/z: 453.1 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([C:25](=[O:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1.O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:22]2[CH2:23][CH2:24][N:19]([C:25](=[O:27])[CH3:26])[CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Yield: 68.8 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (100 mg, 0.32 mmol) and 1-(piperazin-1-yl)ethanone (83 mg, 0.65 mmol) in NMP (1 mL) was heated to 110° C. for 16 h, cooled then diluted with H2O (15 mL) and extracted with ethyl acetate (2×15 mL). The organics were washed with brine (8 mL), dried (Na2SO4) then filtered and concentrated in vacuo. The residue was subjected flash silica column chromatography (100% ethyl acetate) to furnish 1-(4-(3-(benzylamino)-4-nitrophenyl)piperazin-1-yl)ethanone (mg, 0.22 mmol) as a yellow solid (71 mg, 0.19 mmol) 61% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.83 (m, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.39 (m, 4H), 7.28 (m, 1H), 6.40 (dd, J=2.5 Hz, 10 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 4.58 (d, J=6 Hz, 2H) 3.50-3.29 (m, 8H), 2.34 (s, 3H).+ESI HRMS (calcd for C19H22N4NaO3, M+Na) 377.1590, found 377.1584
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:16])([F:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([F:16])[F:15])=[N+:20]=[N-:21]
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(F)(F)c1ccccc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Heat at 60° C. a solution of 2,2-difluoro-2-phenyl-ethyl trifluoromethanesulfonate (759 mg, 2.617 mmol) and sodium azide (357 mg, 5.496 mmol) in anhydrous DMF (10 mL) under nitrogen for 3 h. Cool the reaction mixture to room temperature. Dilute with water and extract the aqueous phase twice with diethyl ether. Wash the combined organic extracts twice with ice-cold water, dry over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as an oil (475 mg, 99%) that was used without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([NH:33][S:30]([C:28]1[CH:27]=[CH:26][C:18]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)=[N:16][C:17]=2[CH:29]=1)(=[O:32])=[O:31])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Product: O=C(NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1)c1ccccc1
Yield: 21.2 %

Procedure:
Intermediate 69 (0.023 g, 0.05 mmol) and benzoyl chloride (0.005 ml, 0.06 mmol) were used to prepare the titled compound (0.006 g, 18%) by the same method as in example 15. 1H NMR (CDCl3) δ 8.59 (s, 1H), 8.26 (d, 1H, J=8.8 Hz), 7.84 (m, 3H), 7.59 (d, 211, J=8.8 Hz), 7.56-7.37 (m, 8H), 7.18 (d, 2H, J=8.4 Hz), 5.17 (s, 2H), 4.42 (m, 1H), 2.33 (br m, 4H), 1.99 (br m, 2H), 1.81 (br m, 1H), 1.36 (br m, 3H); ESI-MS m/e 566.1 (M+1); HPLC purity (ELSD) 100%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)Cl>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:2][NH:1][C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[CH2:12][CH2:11]2
Reactant: COc1cccc2c1OC(CN)CC2
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OC(CNC(=O)C1CCCCC1)CC2
Reaction time: 8 h

Procedure:
A mixture of 9.5 g (49 mmol) of 2-aminomethyl-8-methoxychroman and 4.9 ml (49 mmol) of triethylamine in 50 ml of anhydrous methylene chloride is added dropwise to a solution of 7.2 g (49 mmol) of cyclohexanecarbonyl chloride in 75 ml of anhydrous methylene chloride, while stirring and cooling with ice. After the mixture has been left to stand overnight, it is poured onto ice. Separation of the phases, extraction of the aqueous phase with methylene chloride, washing with saturated sodium chloride solution and drying of the combined organic phases over anhydrous sodium sulphate gives, after evaporation under a water pump vacuum, 14.5 g of crude amide, which is recrystallised from 160 ml of ethyl acetate. IR (KBr): 3307, 2931, 1642, 1485 and 1256 cm
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][S:20]([CH3:19])(=[O:22])=[O:21])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of 2-ethyl-5-nitroaniline (200 mg, 1.20 mmol) in DCM (5 mL) was added pyridine (0.195 mL, 2.41 mmol) and methanesulfonyl chloride (0.11 mL, 1.44 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine and dried to give Intermediate 78A (290 mg, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (1H, d, J=2.26 Hz), 8.04 (1H, dd, J=8.53, 2.26 Hz), 7.44 (1H, d, J=8.53 Hz), 6.59 (1H, br. s.), 3.15 (3H, s), 2.76 (2H, q, J=7.53 Hz), 1.32 (3H, t, J=7.53 Hz).
Reaction SMILES: [I-:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH3:9].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(C(C)C)CC)(C)C>C(#N)C>[I-:1].[N:10]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=2[CH3:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: C[n+]1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[n+]1ccccc1-n1ccnc1

Procedure:
2-Chloro-1-methylpyridinium iodide (9.43 g), imidazole (2.45 g) and diisopropylethylamine (4.77 g) were added to acetonitrile (150 ml) and the mixture refluxed for 2 hours. The product was filtered off from the chilled solution and dried. Yield, 6 g.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=2.ClC1C=NC2C(=CC=C(C(Cl)=O)C=2)N=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][C:22]([C:26]([N:4]([O:3][CH3:2])[CH3:5])=[O:27])=[CH:21][CH:20]=2
Reactant: CNOC
Reactant: O=C(Cl)c1ccc2ncc(Cl)nc2c1
Agent: Cl
Agent: O=C(Cl)c1ccc2nc(Cl)cnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of O,N-dimethyl-hydroxylamine hydrochloride salt (29 g, 0.30 mol, 1.1 eq) and DIEA (182 mL, 1.08 mol, 4.0 eq) in DCM (300 mL) was added the mixture of 3-chloro-quinoxaline-6-carbonyl chloride and 2-chloro-quinoxaline-6-carbonyl chloride (52 g, 0.27 mol, 1.0 eq) at 0° C. The mixture was stirred at rt overnight, then concentrated. The residue was washed with water (300 mL×2) and extracted with EA (300 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting solid was triturated with EA/PE=1/1 (300 mL) to afford 3-chloro-N-methoxy-N-methylquinoxaline-6-carboxamide (16.5 g, 24.3%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][C:33]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)Cc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 14 mL (0.11 mmol) phenylacetyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: Cl[C:2]1[CH:8]=[C:7](S(C)(=O)=O)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O-])(=[O:15])[CH3:14].[NH4+]>>[C:13]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:2]=1)(=[O:15])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=O)Nc1ccccc1

Procedure:
2-Chloro-4-methylsulfonylaniline (2.06 g.) is diazotized and coupled with 3-(N-cyclohexyl-N-ethylamino)acetanilide (2.60 g.) in 40 ml. of 1:5 acid as described in Example 9, except that the coupling is buffered by the addition of ammonium acetate after the diazonium solution is added to the coupler. This azo compound, 2-(2-chloro-4-methylsulfonylphenylazo)-5-N-cyclohexyl-N-ethylamino)acetanilide, produces bright scarlet shades on polyester fibers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][NH2:14].C([O-])(O)=O.[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:14][CH2:13][C:12]([F:11])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NCC(F)(F)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCC(F)(F)c2ccccc2)n1
Temperature: 85 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.66 g, 3.69 mmol), 2,2-difluoro-2-phenyl-ethylamine (0.58 g, 3.69 mmol), and NaHCO3 (0.93 g, 11.1 mmol) in 95% EtOH (10 mL) is heated to reflux. After stirred at 85° C. for 5 h. The mixture is diluted with water, filtered, washed (water), and dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine as a solid (0.58 g). LCMS: RT=3.17 minutes, MS: 300 (M+H). 1H NMR (300 MHz, CDCl3) □7.57-7.45 (5H, m), 6.1 (1H, s), 5.2 (1H, s), 4.2-4 (2H, m), 3.92 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]([C@:30]1(C)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=O.C(Cl)Cl>C(OCC)C>[CH3:28][C@@:30]1(/[CH:8]=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: C(Cc1ccccn1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@]1(/C=C/c2ccccn2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 353 mg (1.0 mmol) of (2-picolyl)methylene-triphenylphosphorane and 381 mg (1.00 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo-[3.2.0]heptane-2-carboxylate in 10 ml of diethyl ether was stirred at room temperature under argon for 2 hours. The mixture was treated with 10 ml of methylene chloride, insoluble material was removed by suction filtration and the filtrate was concentrated. The residue remaining behind was chromatographed over silica gel (particle size 0.040-0.063 mm) with methylene chloride:ethyl acetate (95:5) as the eluent.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[K+].[CH2:22]([SH:24])[CH3:23]>CN(C)C=O.C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([S:24][CH2:22][CH3:23])[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCSc1nc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A solution of 3.40 g (12 mmol) 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 60 ml N,N-dimethylformamide heated to 60° C. was treated with a solution of 3.36 g (60 mmol) potassium hydroxide and 6 ml (81 mmol) ethanethiol in 30 ml absolute ethanol. After stirring 15 minutes at 60° C. the mixture was poured into 240 ml ice cold 0.5 N hydrochloric acid, and the precipitate was filtered, washed with water and crystallized from acetic acid--water to give 3.10 g, mp 242°-244° C. of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:11][NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C@H:12]1[CH2:11][NH:10][C:9](=[N:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29])[C@@H:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: NCC(O)CC(F)(F)F
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=NCC(O)CC(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl[(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (75.0 mg, 0.219 mmol) in ethanol (2.19 mL) was added the hydrochloride salt of 1-amino-4,4,4-trifluorobutan-2-ol (98.0 mg, 0.548 mmol), mercury(II) chloride (77.0 mg, 0.285 mmol), and triethylamine (73.3 uL, 0.526 mmol). The mixture was stirred 10 min, filtered, and concentrated giving the crude title compound. MS 452.17 (M+1).