Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]([CH3:27])([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:29][NH2:30]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]([CH3:27])([CH3:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-{2-amino-6-[(1,1-dimethyl-2-phenylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (210 mg, 0.58 mmol) and hydrazine hydrate (99%, 2 mL) in ethanol (3 mL) was stirred and heated at 120° C. for 1 h in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated in vacuo. Water (100 mL) was added, and the resulting mixture was filtered. The solids were dried under vacuum to afford the title compound (90 mg) as a yellow solid. LC-MS (ES) m/z=374 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.34 (s, 6H), 3.26 (s, 2H), 5.37 (s, 2H), 6.05 (s, 2H), 6.34 (s, 1H), 6.40 (s, 1H), 7.10-7.25 (m, 5H), 7.39 (d, 1H), 7.70 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: O[CH:2]1O[C:5](=[O:7])[C:4]2[CH:8]=[C:9]3[C:14](=[C:15]([O:16][CH3:17])[C:3]1=2)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]2[C:5](=[O:7])[C:4]3[CH:8]=[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]4=[C:15]([O:16][CH3:17])[C:3]=3[CH2:2]2)=[CH:24][CH:23]=1)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: COc1c2c(cc3ccccc13)C(=O)OC2O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2Cc3c(cc4ccccc4c3OC)C2=O)cc1
Reaction time: 24 h
Yield: 54.5 %

Procedure:
3-Hydroxy-4-methoxynaphtho[2,3-c]furan-1(3H)-one (50 mg, 0.22 mmol) and ethyl 4-aminophenylacetate (47 mg, 0.26 mmol) in dichloromethane (5 ml) were stirred at room temperature under nitrogen for 1 hour. Sodium triacetoxyborohydride (138 mg, 0.66 mmol) was added and stirring continued for 24 h. The reaction was adjusted to pH14 with sodium hydroxide solution (2N) and extracted with dichloromethane (3×5 ml). The combined extracts were evaporated under vacuum and the residue triturated with cyclohexane/ether to give ethyl[4-(4-methoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate as a white solid (45 mg, 54%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][CH3:18])[CH:13]=[CH:12][C:11]=2[C:10]2[N:19]=[C:20](Br)[CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:76]1[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCOCC1>[CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][CH3:18])[CH:13]=[CH:12][C:11]=2[C:10]2[N:19]=[C:20]([N:76]3[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]3)[CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(Br)nc2c3ccc(OC)cc3n(Cc3ccccc3)c12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(N2CCCCC2)nc2c3ccc(OC)cc3n(Cc3ccccc3)c12
Temperature: 100 °C
Yield: 57.1 %

Procedure:
A vial containing a mixture of methyl 5-benzyl-2-bromo-7-methoxy-5H-pyrido[3,2-b]indole-4-carboxylate (90 mg, 0.21 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (18 mg, 0.032 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (11 mg, 11 μmol), Cs2CO3 (56 mg, 0.53 mmol) was flushed with nitrogen. Dioxane (1 mL) and piperidine (0.042 mL, 0.42 mmol) was added and the vial was sealed and heated at 100° C. overnight. This was then diluted with EtOAc, washed with water and brine, and dried over Na2SO4. Removal of the solvent followed by radial silica gel chromatography (step gradient elution with DCM containing 0 to 2% MeOH) afforded methyl 5-benzyl-7-methoxy-2-(piperidin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (51 mg, 0.12 mmol, 56% yield) as a solid. MS (ESI) m/z 430.2 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.15 (1H, d, J=8.55 Hz), 7.25 (1H, s), 7.15-7.21 (2H, m), 6.89-6.94 (3H, m), 6.87 (1H, dd, J=8.55, 2.14 Hz), 6.78 (1H, d, J=2.14 Hz), 5.59 (2H, s), 3.84 (3H, s), 3.66 (3H, s), 3.53-3.61 (4H, m), 1.68-1.76 (4H, m), 1.61-1.68 (2H, m).
Reaction SMILES: CS(C)=O.[C:5]([C:7]1[CH:27]=[CH:26][C:10]2[O:11][C:12]([CH3:25])([CH3:24])[CH:13]=[C:14]([N:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][C:16]3=[O:23])[C:9]=2[CH:8]=1)#[N:6].C(N(CC)CC)C.O>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[C:5]([C:7]1[CH:27]=[CH:26][C:10]2[O:11][C:12]([CH3:24])([CH3:25])[CH:13]=[C:14]([N:15]3[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:16]3=[O:23])[C:9]=2[CH:8]=1)#[N:6]
Reactant: CC1(C)C=C(n2ccc(CO)cc2=O)c2cc(C#N)ccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)C=C(n2ccc(C=O)cc2=O)c2cc(C#N)ccc2O1
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
In 200 ml of anhydrous methylene chloride, is dissolved 3.84 ml of oxalyl chloride. After cooling the resulting solution to -50° C. to -60° C., 6.24 ml of dimethyl sulfoxide is dropped thereinto and stirred at that temperature for 5 minutes. Then, 200 ml of a solution containing 12.3 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 9 (or Example 22) in anhydrous methylene chloride is added at that temperature over a period of 25 minutes and reacted at that temperature for 20 minutes. After adding 27.9 ml of triethylamine to the reaction mixture and stirred at that temperature for 10 minutes, the temperature is slowly elevated to room temperature. After stirring the mixture at room temperature for an additional one hour, the reaction is stopped by adding water, and the reaction mixture is extracted with methylene chloride. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/30 mixture of methanol/methylene chloride as a developing solvent. Thus, 12.2 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-formyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])[S:5][CH:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][C:2]1[C:3]2[C:10]([CH3:11])=[N:9][CH2:8][CH2:7][C:4]=2[S:5][CH:6]=1
Reactant: CC(=O)NCCc1cc(C)cs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2scc(C)c21

Procedure:
In close analogy to the procedure described above, N-[2-(4-Methyl-thiophen-2-yl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.Cl.CCN(C(C)C)C(C)C.Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>CC(N(C)C)=O>[CH3:1][N:2]([C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1
Reactant: CNCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)c1nccc(C(F)(F)F)n1

Procedure:
A solution of 0.250 g (1.13 mmol) of trans-4-(2-methylamino-ethyl)-cyclohexanecarboxylic acid•HCl, 1.04 mL (6.09 mmol, 5.3 eq) of Huenig's base and 0.412 g (2.26 mmol, 2 eq) of 2-chloro-4-(trifluoromethyl)pyrimidine in 4 mL of DMA were reacted at RT for 19 h. The solvent was evaporated and the residue partitioned between Et2O (×3)/aqueous 10% KH2PO4, dried over Na2SO4, and evaporated to yield 0.422 g (quantitative) of trans-4-{2-[methyl-(4-trifluoromethyl-pyrimidin-2-yl)-amino]-ethyl}-cyclohexanecarboxylic acid, MS: 330 (M−H−), MP: 110-112° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:21])[NH:15]C(OCC)=O)=O>CN(C)C=O>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]1[C:6]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:12])[CH:11]=2)[NH:13][C:14](=[O:21])[N:15]=1
Reactant: CCOC(=O)NC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccc2F)c2cc(Cl)ccc2[nH]1

Procedure:
Ethyl 4-(2-(o-fluorobenzoyl)-4-chlorophenyl)-allophanate (50 mg) was dissolved in dimethylformamide and the mixture was heated to the reflux temperature to deposit crystals. The crystals were collected by filtration and dried to give 4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone having a melting point of over 300° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:18][CH2:19][CH2:20][CH2:21]/[C:22](=[CH:26]\[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]2)=[C:29]([O:39][CH3:40])[CH:28]=1)/[C:23]([OH:25])=O.[C:41]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])[NH:42][NH2:43].C(N(C(C)C)CC)(C)C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[Cl:18][CH2:19][CH2:20][CH2:21]/[C:22](=[CH:26]\[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]2)=[C:29]([O:39][CH3:40])[CH:28]=1)/[C:23]([NH:43][NH:42][C:41]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:25]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C(\CCCCl)C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
HOBT (108 mg) and EDC (153 mg) were sequentially added to a solution of 5-chloro-2-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}valeric acid trifluoroacetic acid salt (300 mg), tert-butyl carbazate (71 mg) and IPEA (0.38 mL) in DMF (5 mL), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 222 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([S:21][CH3:22])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: CSc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 52 %

Procedure:
2,3,4-Trifluorobenzoic acid and the product of Example 26, Step B, 2-fluoro-4-methylthioaniline, were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, this material was purified by dry flash column chromatography on silica (0.5% Et2O in 1:1 CH2Cl2/hexanes as eluant) to afford 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]benzoic acid as a cream solid (52%); m.p. (Et2O/hexanes) 210–220° C. 1H NMR (400 MHz, CDCl3) δ 13.70 (br s, 1 H), 9.24 (br s, 1 H), 7.81 (ddd, J=9.0, 6.1, 2.1 Hz, 1 H), 7.20 (dd, J=11.8, 1.9 Hz, 1 H), 7.03–6.99 (m, 3 H), 2.47 (s, 3 H). Anal. Calcd for C14H10F3NO2S.0.125 Et2O: C, 54.0; H, 3.5; N, 4.3. Found: C, 54.2; H, 3.3; N, 4.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(F)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]CC)=[O:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1.[OH-].[K+]>>[C:22]([C:18]1[C:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)=[C:2]([Cl:1])[CH:21]=[CH:20][CH:19]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)Cc1ccc(OCc2c(Cl)cccc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2c(Cl)cccc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-chloro-6-ethoxycarbonylbenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(6-carboxy-2-chlorobenzyloxy)phenylacetic acid as a colorless solid, mp 171°-173° C.
Reaction SMILES: [Na:1].CC1(C)COC(CO[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])OC1.ClC1C=C[N+]([O-])=C(C)C=1C.[F:41][C:42]1([F:50])[CH2:47][O:46][CH:45]([CH2:48][OH:49])[O:44][CH2:43]1>>[Na:1].[F:41][C:42]1([F:50])[CH2:47][O:46][CH:45]([CH2:48][O:49][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])[O:44][CH2:43]1
Reactant: OCC1OCC(F)(F)CO1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: Cc1c(OCC2OCC(F)(F)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 22.7 %

Procedure:
The same procedure as in the steps (1c) to (1g) of Example 1 was repeated using 4-chloro-2,3-dimethylpyridine 1-oxide and (5,5-difluoro-1,3-dioxan-2-yl)methanol to obtain the title compound (375 mg, 5 steps: 22.7%) as a white powder.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C>O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:26]([OH:28])=[O:27]
Reactant: O=C(O)Cc1ccccc1F
Reactant: CSc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ccc(C=C(C(=O)O)c2ccccc2F)cc1
Temperature: 90 °C
Yield: 62.9 %

Procedure:
Acetic anhydride (60 mL), 4-(methylthio)benzaldehyde (7.05 g, 44 mmol), 2-fluorophenylacetic acid (7.79 g, 50.5 mmol), and triethylamine (5.50 g, 54.5 mmol) were placed in a 250 mL round bottom flask and heated to reflux for 1.75 hours. The reaction was cooled to 90° C., and water (100 mL) was added cautiously through an addition funnel. This caused the solution to reflux vigorously and the temperature to rise to 135° C. A yellow precipitate formed and after cooling to room temperature the solid was collected by filtration, washed with water, and recrystallized from toluene to provide 2-(2-fluorophenyl)-3-(4-methylthiophenyl)propenoic acid as yellow needles (7.98 g, 63%): mp 151.5°-156.0° C. 1H NMR (CDCl3) 300 MHz 8.01 (s,1H), 7.41-7.00 (m, 8H), 2.43 (s, 3H). 19F NMR (CDCl3) -113.40 (m). Mass spectrum M+H+ =289.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>[OH-].[Na+].C(OCC)C>[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
Glycine (1 g, 13.32 mmol) was dissolved in 1N NaOH (aq.) and a solution of tosyl chloride (2.62 g, 13.72 mmol) in diethyl ether (15 ml) was added portion wise with stirring over 10 min. The resulting mixture was allowed to stir at room temperature for 3 h. The ethereal layer was separated and the aqueous layer treated with 2N HCl solution until acidified to pH 5. After cooling the resulting solution to 0° C., the product began to precipitate from the solution. The solid was collected by filtration and the mother liquor placed in a fridge overnight causing more of the desired product to precipitate. The solid was again collected by filtration and the combined collected solid was dried under high vacuum affording 9 as a white powder (613 mg, 21%). δH (400 MHz, MeOD) 2.41 (3H, s, CH3), 3.66 (2H, s, CH2), 7.35 (2H, d, J=8 Hz, ArH), 7.73 (2H, d, J=8 Hz, ArH); δc (100.6 MHz, MeOD) 20.3, 43.6, 127.0, 129.5, 137.6, 143.6, 171.0; MS (ES+) 246.8 (100%, [M+H2O]+); MS (ES−) 227.9 (100%, [M−H]−); HRMS [M−H]− requires 228.03360, found 228.03364.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:43])([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(F)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester, from Example 511, (80 mg, 0.16 mmol) in DCM (8 mL) at −78° C. was added DAST (200 μL, 1.52 mmol). The reaction mixture was stirred at −78° C. for 30 min then allowed to warm to RT and stirred for 16 h. The reaction mixture was stirred at RT for 16 h then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in DCM) to give 4-Fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (45 mg, 56%). LCMS: RT=5.05 min, [M+H]+=514
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([O:35]C(OC(C)(C)C)=O)[C:25]([C:43]([F:46])([F:45])[F:44])=[CH:24][CH:23]=1>>[C:31]([O:30][C:28]([C:27]1[C:26]([OH:35])=[C:25]([C:43]([F:44])([F:45])[F:46])[CH:24]=[CH:23][C:22]=1[CH2:21][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:7][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)ccc(C(F)(F)F)c1O
Yield: 15 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl (2-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (150 mg, 0.54 mmol) obtained in Example (23-3) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (455 mg, 1.0 mmol) obtained in Example (28-5), the title compound was obtained as a colorless compound (46 mg, three-step total yield: 15%).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([S:56][CH3:57])[N:53]=[C:52]([S:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:61]=2[F:67])[N:51]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:67][C:61]1[C:62]([F:66])=[CH:63][CH:64]=[CH:65][C:60]=1[CH2:59][S:58][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([S:56][CH3:57])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CSc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.32 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.58 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-(methylthio)pyrimidine (the product of example 57, step i) (0.38 g) in dioxane (10 mL) was heated at 100° C. for 18 h. The mixture was cooled and saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give the title compound as a white solid. Yield: 50 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cncc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.6 %

Procedure:
To a mixture of 2-(5-bromo-pyridin-3-yl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (16 g, 39.5 mmol) and triethylsilane (40 mL) at 25° C. was added trifluoroacetic acid (20 mL) dropwise. The resulting mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 2-(5-bromo-pyridin-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.4 g, 28%) as a yellow solid: LC/MS m/e calcd for C19H21BrN2O2 (M+H)+: 390.30, observed: 390.9.