Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:37])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH:21]([NH:29]C(=O)OC(C)(C)C)[CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38].O>O1CCOCC1>[NH2:29][CH:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:17])=[O:18])[CH2:20]1.[ClH:38]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 1-(4-(3-phenylureido)phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate in 1,4-dioxane (1 mL) was added 4 M hydrogen chloride in 1,4-dioxane (2 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 20 hours. Water (1.5 mL) was added and the mixture extracted with ethyl acetate (3×1.5 mL). The combined organics were dried over sodium sulfate and concentrated to give 1-(4-(3-amino-3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl)-3-phenylurea as its HCl salt.
Reaction SMILES: [Li+].[Cl-].[CH2:3]([O:5][C:6](=[O:23])[CH:7]([C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][N:14]=1)C(OCC)=O)[CH3:4]>CS(C)=O.O>[CH2:3]([O:5][C:6](=[O:23])[CH2:7][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][N:14]=1)[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncc(C)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 3 h

Procedure:
LiCl (10.6 g, 0.252 mol) is suspended in a solution of 2-(5-Methyl -3-nitro-pyridin-2-yl)-malonic acid diethyl ester (50 g, 0.168 mol) in DMSO (100 mL) containing water (12 g, 0.678 mol) and is stirred at 150° C. for 3 h. The reaction mixture is cooled, diluted with water (200 mL), and extracted with ethyl acetate. The combined organic phase are washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20% EtOAc-hexanes to afford (5-Methyl-3-nitro-pyridin-2-yl)-acetic acid ethyl ester as an oil; 1H NMR (300 MHz, CDCl3) δ 1.23 (t, J=9 Hz, 3H), 4.15 (q, J=9 Hz, 2H), 4.25 (s, 2H), 8.2 (s, 1H), 8.58 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]1([CH3:28])[C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:27])[O:15]1>>[CH3:13][C:14]1([CH3:28])[C:19]2[CH:20]=[C:21]([C:2]3[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=3)[CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:27])[O:15]1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: CC(=O)Nc1ccc(Br)cc1F
Product: CC(=O)Nc1ccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)cc1F

Procedure:
Prepared according to procedure B from 4′-bromo-2′-fluoroacetanilide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Off white solid; mp 245-247° C. 1H-NMR (DMSO-d6) δ10.3 (s,1H), 9.79 (s, 1H), 7.95 (t,1H; J=8.4 Hz), 7.56-7.63(m,3H), 7.47(dd,1H J=1.64, 8.47 Hz), 6.95(d,1H; J=8.9 Hz), 2.1(s, 3H), 1.67(s,6H); MS+APCI [M+H]+ m/z 329. Anal. Calc. For C18H17N2 FO3: C, 65.85, H, 5.22, N, 8.53. Found: C,65.46, H,5.24, N,8.12.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][OH:22])[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([O:46][C:47]([N:49]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:50]1[N:58]=[C:57]2[C:53]([N:54]=[CH:55][N:56]2O)=[C:52]([O:60][CH3:61])[N:51]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:65]([O:64][C:62]([N:49]([C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:48])[C:50]1[N:58]=[C:57]2[C:53]([N:54]=[CH:55][N:56]2[O:22][CH2:21][C@@H:10]([O:11][CH2:12][P:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:20])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:52]([O:60][CH3:61])[N:51]=1)=[O:63])([CH3:68])([CH3:67])[CH3:66]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Reactant: CCOP(=O)(CO[C@H](CO)COCc1ccccc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CO[C@@H](COCc1ccccc1)COn1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred solution of diethyl (R)-[2-benzyloxy-1-(hydroxymethyl)ethoxy]methylphosphonate (1.0 g, 3 mmol), triphenylphosphine (1.18 g, 4.5 mmol) and 2-[bis-(t-butoxycarbonyl)amino]-9-hydroxy-6-methoxypurine (1.15 g, 3 mmol) in dry THF (20 ml), cooled in ice and under a mitrogen atmosphere, was added, dropwise, diethyl azodicarboxylate (0.71 ml, 4.5 mmol). The resulting solution was allowed to warm to ambient temperature and left stirring for 16 hours. The solvent was evaporated under reduced pressure and the residue obtained chromatographed on silica gel using hexane/ethyl acetate 2:1 as eluant. The eluant was changed as follows: hexane/ethyl acetate 1:1, hexane/ethyl acetate 1:2 and finally to ethyl acetate to give (S)-2-[bis-(t-butoxycarbonyl)amino]-9-[3-benzyloxy-2-(diethoxyphosphorylmethoxy)propoxy]-6-methoxypurine as a colourless oil (1.85 g, 88%).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)[CH3:15].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([CH2:14][CH3:15])=[CH:17][CH:18]=1)[CH2:11]2
Reactant: CCc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 4-ethyl-benzylamine (0.072 mL, 0.5 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.032 g, 28%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.51 (q, 2H), 4.14 (s, 2H), 4.76 (s, 2H), 7.14-7.38 (m, 6H), 7.86 (d, 1H). GC-MS: m/z 377 (M)+, 348 (M−29)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[C:6]([C:7]#[N:8])=[CH:16][N:17]([CH3:18])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1ccccc1Cl
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1Cl

Procedure:
As for Example 1, 2'-chloro-2-cyanoacetanilide, white crystalline product, m.p. 122.5°-123° C. (prepared as described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-chloro-2-cyano-3-dimethylaminoacrylanilide as colorless prisms, m.p. 104°-105° C.
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[N:13][C:14]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[C:19]([Cl:32])[CH:18]=2)[NH:9][N:8]=1>O.C(O)C>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:14]2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][N:8]=[C:7]([O:6][CH2:5][CH2:4][NH:2][CH3:1])[C:15]=23)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: CN
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Solvent: CCO
Solvent: O
Product: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 120 °C
Yield: 14 %

Procedure:
Methylamine in water (40% solution, 2 ml) was added to a suspension of 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 12/0.4 g, 0.89 mmol) in ethanol (4 ml) and the reaction mixture was heated at 120° C. for 5 minutes in a microwave reactor. The resulting solution was concentrated in vacuo and the residue purified by chromatography using DCM to DCM-10% methanol/7N ammonia as eluant to give the title compound as a white solid (57 mg, 14%); Mass Spectrum: 443.3 (MH+/retention time 1.5 minutes).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=4[Cl:68])[C:62](O)=[O:63])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1>C1COCC1.O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([C:62]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[O:63])[CH:65]=[CH:66][C:67]=4[Cl:68])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(Cl)c(N(C)C(=O)c3cc4c(s3)-c3ccc(Br)cc3OCC4)c2)CC1
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a mixture of 1-methyl-piperazine (1.22 g, 12.18 mmol), DIPEA (3 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3.0 g, 6.09 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo to give 8-bromo-N-(2-chloro-5-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (3.3 g, yield 94%)1H NMR (DMSO-d6, 400 MHz): δ7.74-7.21 (m, 6H, ArH), 6.67 (s, 1H, ═CH), 4.18 (t, J=4.4 Hz, 2H, CH2), 3.31-2.12 (m, 16H, CH3, CH2)
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[C:20]([C:18]1[CH2:17][N:13]2[CH:14]=[CH:15][C:16]3[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=3)=[C:12]2[N:19]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(=Cc1cccn2cc(C(C)(C)C)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(C(C)(C)C)=N3

Procedure:
From 6g (yield: 57%); mp 276-278° C.; IR (KBr) 1711, 1243, 1175 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.38 (m, 12H), 4.36 (q, 2H, J=7 Hz), 6.97 (d, 1H, J=7 Hz), 7.36 (s, 1H), 7.56 (s, 1H), 8.21 (d, 1H, J=7 Hz), 12.43 (brs, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.2, 30.1, 31.8, 60.3, 100.6, 106.6, 107.2, 113.2, 124.2, 125.5, 124.2, 125.5, 133.0, 140.1, 153.2, 160.6; MS m/z 285 (M+, 57), 270 (38), 224 (100), 196 (17). Anal. Calcd for C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.20; H, 6.88; N, 14.51.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[O:12]=[C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]3)[C:11]=2[O:10][CH2:9]1
Reactant: O=C1COc2c(CBr)cccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
A solution of 7-bromomethylbenzofuran-3(2H)-one (0.573 g, 2.52 mmol) in methylene chloride (20 mL) was added with sodium acetate (0.412 g, 5.03 mmol) and 1-tert-butoxycarbonylpiperazine (0.721 g, 3.87 mmol), and the mixture was stirred at room temperature for 6 hours. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.391 g, 46%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[N:16]=CC1C=CC=CC=1)=[O:14])[CH3:2]>[Pd].COCCOC>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[NH2:16])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Agent: [Pd]
Solvent: COCCOC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a 25 mL volume two-necked flask, 1.47 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5), 5.1 ml of 1,2-dimethoxyethane and 147 mg of 5 wt % Pd—C were added. The mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. An unsolved substance was removed by filtration and washed with 1,2-dimethoxyethane. The filtrates were combined and concentrated under reduced pressure to give 1.068 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39).
Reaction SMILES: [NH2:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[I:7][C:6]1[C:2]([NH:1][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1onc(N)c1I
Product: Cc1onc(NS(=O)(=O)c2ccccc2)c1I

Procedure:
N-(4-Iodo-5-methyl-3-isoxazolyl)benzenesulfonamide was prepared from 3-amino-4-iodo-5-methylisoxazole and benzenesulfonyl chloride according to the procedures described in Example 2b. The crude product was purified by recrystalization from ethyl acetate/hexanes to give a brown powder m.p. 138°-141° C., yield 46%.
Reaction SMILES: [CH:1]1([C:4]([CH:6]2[CH2:8][CH2:7]2)=O)[CH2:3][CH2:2]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>O1CCCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH:1]1([C:4]([CH:6]2[CH2:8][CH2:7]2)=[N:15][S@@:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(C1CC1)C1CC1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C(C1CC1)C1CC1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 22.3 %

Procedure:
A 20-mL microwave vial containing a solution of dicyclopropyl ketone (0.778 ml, 6.81 mmol), (R)-2-methylpropane-2-sulfinamide (0.825 g, 6.81 mmol), and titanium ethoxide (1.427 ml, 6.81 mmol) in tetrahydrofuran (13.5 mL) under argon was heated in a microwave for 5 minutes at 150° C. and then again at 160° C. for an additional 5 minutes. The reaction mixture was poured into brine (14 mL), the resulting slurry filtered through Celite, and the two resulting layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography (10-50% ethyl acetate/hexanes) to afford (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.325 g, 1.52 mmol, 22% yield). MS ESI: [M+H]+ m/z 214.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][C:11]=1[Cl:25]>O1CCCC1>[C:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([Cl:25])[CH:12]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CO)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
Add 1M lithium aluminum hydride in tetrahydrofuran (32 mL, 32 mmol) to anhydrous tetrahydrofuran (240 mL) at room temperature under argon gas, cool to 0° C. and add slowly a solution of 4-(tert-butoxycarbonylamino-methyl)-2-chloro-benzoic acid methyl ester (3.2 g, 10.7 mmol) in tetrahydrofuran (120 mL). The reaction mixture is stirred at 0° C. for 45 min. Quench the reaction mixture with saturated aqueous ammonium chloride and extract with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by chromatography (silica gel) eluting with 35% ethyl acetate/hexane to give the title compound (2.1 g, 7.7 mmol). MS (m/z): 294 (M+23).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O-:13])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[K+].[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[O:35].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C=O)C>[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:2]3[CH:3]=[C:4]([C:8]4([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]4)[CH:5]=[N:6][CH:7]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[O:35]
Reactant: O=C([O-])C1(c2cncc(Br)c2)CC1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(-c3cncc(C4(C(=O)O)CC4)c3)ccc21
Temperature: 120 °C
Yield: 112.5 %

Procedure:
A flask was charged with potassium 1-(5-bromopyridin-3-yl)cyclopropanecarboxylate (0.5 g, 1.52 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1, 0.479 g, 1.67 mmol) and DMF (7 mL). Then, bis(triphenylphosphine)palladium(II)chloride (0.106 g, 0.152 mmol), followed by 1N aqueous Na2CO3 solution (3.64 mL, 2.4 mmol) were added and the reaction was heated to 120° C. (pre-heated oil bath) for 1 h. The mixture was evaporated to dryness and the residue purified by silica gel flash chromatography eluting with a 0 to 15% MeOH-DCM gradient to give the title compound (0.551 g, 100%) as a brown solid. MS: 323.4 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:29]=[CH:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C:19]=3[CH:18]=2)\[CH3:16])=[CH:8][CH:7]=1)C.CO>[OH-].[Na+]>[CH:18]1[C:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][C:17]=1/[C:15](/[CH3:16])=[CH:14]/[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:30])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(OC/C=C(\C)c2ccc3c(c2)Cc2ccccc2-3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=C\COc1ccc(CC(=O)O)cc1)c1ccc2c(c1)Cc1ccccc1-2
Reaction time: 24 h
Yield: 75.6 %

Procedure:
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl ester (example 16) (193 mg, 0.5 mmol) was suspended in 1N NaOH (5.0 mL) and methanol (5 mL) and stirred for 16 h at room temperature. A 2nd portion and 1N NaOH was added and stirring continued for 24 h. The mixture was concentrated to 10 mL volume then diluted with 1N HCl (50 mL) and ethyl acetate (150 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL) The organic layers were combined, dried (NaSO4) and evaporated. The residue was recrystallised from ethyl acetate (50 ml) to give 140 mg (75%) of the title compound as an pale yellow powder.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:25][C:24]=3[CH3:26])[CH2:20][CH2:21]2)[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: COc1cc(C)c2c(c1)CCN2c1nc(Cl)cn(CCSC)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 111-113° C.; 1H NMR (300 MHz, CDCl3): δ 6.80 (s, 1 H), 6.68 (d, J=2.2 Hz, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.40 (t, J=7.7 Hz, 2 H), 4.04 (t, J=7.1 Hz, 2 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.89 (t, J=7.2 Hz, 2 H), 2.18 (s, 3 H), 2.06 (s, 3 H); HRMS (CI) calcd for C17H20N3O2SCl (M+): 365.0965; found m/z 365.0967.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:3].[N+:12]([O-])([OH:14])=[O:13]>CS(O)(=O)=O>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:1]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Product: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromoacetanilide (20 g, 93.4 mmol) in methanesulfonic acid is cooled to 10° C. Conc. nitric acid (12.6 ml) is added and the mixture is stirred at 40° C. for 2 hours. The mixture is poured into ice-water. The product is filtered off, washed with water and dried. Yield: 23.59 g (97%). Mp 99-100° C.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:22]([NH2:23])=[CH:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: CS(C)(=O)=O
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)C=C(N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of dimethylsulphone (8.3 g), in dry tetrahydrofuran (150 ml) was added dropwise to a stirred ice-cold solution of butyllithium (30 ml of 2.6M solution in hexane). The mixture was stirred at room temperature for 15 minutes and then a solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (15 g) in tetrahydrofuran (25 ml) was added over 15 minutes and the resulting solution was heated under reflux for 16 hours. The solution was cooled and treated with water and the organic layer separated. The aqueous layer was extracted with ether and the ether extracts combined with the previously separated organic layer, dried and the solvents were removed by evaporation. The resulting oil crystallised, and the solid was washed with petroleum ether (b.p. 40°-60° C.) to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-methylsulphonylvinylamine (m.p. 125°-126°).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC(C)([O-])C.[K+].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[Cl:1][C:2]1[N:10]=[C:9]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(OCC(F)(F)F)nc1Cl
Reaction time: 120 h

Procedure:
A mixture of 2,6-dichloronicotinic acid (3.0 g, 15.6 mmol) and potassium tert-butoxide (5.26 g, 46.9 mmol) in 2,2,2-trifluoroethanol (52 mL) is refluxed with stirring for 5 days. After removal of solvent, the residue is dissolved in water (40 mL) then 2M hydrochloric acid (10 mL) is added. White precipitate is filtrated and dried to give 4.08 g of the title compound including 6-chloro-2-(2,2,2-trifluoroethoxy)nicotinic acid and 2,6-bis(2,2,2-trifluoroethoxy)nicotinic acid as a white solid. This material is used for the next reaction (Step-2) without further purification.