Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71]([C:72]([F:75])([F:74])[F:73])=[CH:70][N:69]=[C:68]([NH:76][C:77]4[CH:91]=[CH:90][C:80]([CH2:81][P:82](=[O:89])([O:86]CC)[O:83][CH2:84][CH3:85])=[CH:79][C:78]=4[O:92][CH3:93])[N:67]=3)=[C:61]([C:94](=[O:97])[NH:95][CH3:96])[C:60]=2[O:98][CH3:99])[CH:56]=[N:55]1>>[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71]([C:72]([F:74])([F:73])[F:75])=[CH:70][N:69]=[C:68]([NH:76][C:77]4[CH:91]=[CH:90][C:80]([CH2:81][P:82](=[O:86])([OH:89])[O:83][CH2:84][CH3:85])=[CH:79][C:78]=4[O:92][CH3:93])[N:67]=3)=[C:61]([C:94](=[O:97])[NH:95][CH3:96])[C:60]=2[O:98][CH3:99])[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(OC)c3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(OC)c3C(=O)NC)n2)c(OC)c1

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-3-methoxy-2-(methyl carbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxy benzyl)phosphonate (Compound 30B). 1H NMR (CD3OD, 400 MHz): δ 8.27 (s, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.02 (s, 1H), 6.69 (d, J=8.1 Hz, 1H), 4.33 (t, J=6.8 Hz, 2H), 3.88 (s, 3H), 3.82 (m, 2H), 3.64 (s, 3H), 3.59 (t, J=6.1 Hz, 2H), 2.92 (s, 3H), 2.91 (d, J=20.2 Hz, 2H), 2.11 (m, 2H), 1.13 (t, J=7.1 Hz, 3H). MS (ESI): m/z=694.22 [M+H]+. UPLC: tR=1.09 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:22]([CH:24]=O)=O.S(=O)(O)[O-].[Na+].[OH-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:15]=[C:16]4[C:17](=[CH:18][CH:19]=3)[N:20]=[CH:24][CH:22]=[N:21]4)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=CC=O
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccc2nccnc2c1)c1cccc2cnccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a suspension of 4-(5-Isoquinolylsulfonyl)-1,2-benzenediamine 300 mg (1.0 mmol) in water, a 40% glyoxal solution 450 mg (3.1 mmol) and sodium bisulfite 650 mg (3.1 mmol) and water 8 ml were added, and the mixture was heated with stirring for 2 hours at 80° C. The reaction mixture was alkalized with 1N sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:acetone=5:1), and 6-(5-isoquinolylsulfonyl)quinoxaline 210 mg (66.3%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a solution of ethyl 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (C4, 0.90 g) in ethanol (10 mL) and tetrahydrofuran (5 mL), 2.0 mol/L aqueous sodium hydroxide (2.8 mL) was added at room temperature, and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was cooled to room temperature, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C5, 738 mg).
Reaction SMILES: Cl.ClC1C=CC=C[C:4]=1[N:9]1C=NN=[C:10]1C1SC2C3C=CC(N)=CC=3OCCC=2C=1.CCN(C(C)C)C(C)C.ClCC(Cl)=O.Cl[CH2:44][C:45]([NH:47][C:48]1[CH:49]=[CH:50][C:51]2[C:57]3[S:58][C:59]([C:61]4[N:65]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=5[Cl:72])[CH:64]=[N:63][N:62]=4)=[CH:60][C:56]=3[CH2:55][CH2:54][O:53][C:52]=2[CH:73]=1)=[O:46].Cl.N(C)C.CCN(CC)CC>C(Cl)Cl>[Cl:72][C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=1[N:65]1[CH:64]=[N:63][N:62]=[C:61]1[C:59]1[S:58][C:57]2[C:51]3[CH:50]=[CH:49][C:48]([NH:47][C:45](=[O:46])[CH2:44][N:9]([CH3:10])[CH3:4])=[CH:73][C:52]=3[O:53][CH2:54][CH2:55][C:56]=2[CH:60]=1
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Agent: CNC
Agent: Cl
Agent: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
To a solution of 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-amine HCl salt (0.5 g, 1.16 mmol) in dried DCM (30 mL) was added DIPEA (0.61 mL, 3.48 mmol). The solution was stirred at 0° C. for 20 min and 2-chloro-acetyl chloride (0.2 g, 1.74 mmol) was added dropwise. The mixture was allowed to reach room temperature and stirred for a further 2 hours. The reaction solution was poured into ice water and extracted with EtOAc. The organics were combined, dried over Na2SO4 and evaporated in vacuum to afford the crude product (0.45 g, yield: 82%). 2-chloro-N-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)acetamide (0.2 g, 0.424 mmol) was mixed with HCl salt of NH(CH3)2 (0.172 g, 2.12 mmol) and NEt3 (0.3 mL, 2.12 mmol) in 15 mL of DCM. The solution was stirred at room temperature for 4 hours and quenched with ice water. Extraction with EtOAc and evaporation of the organics gave the crude product. It was purified by preparative TLC to afford 237 (40 mg, isolated yield: 20%). 1H NMR (DMSO-d6, 400 MHz): δ 9.81 (s, 1H), 8.81 (s, 1H), 7.79-7.38 (m, 7H), 6.55 (s, 1H), 4.16 (t, J=5.2 Hz, 2H), 3.02 (s, 3H), 2.96 (t, J=5.2 Hz, 2H), 2.21 (s, 6H). MS: (ESI+) 480.1
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=2)[N:39]=[C:38]([N:47]2[CH2:51][C:50]([CH3:53])([CH3:52])[CH2:49][C:48]2=[O:54])[C:37]=1[CH3:55].[NH2:56][C:57]1[CH:58]=[C:59]([NH:69][C:70](=[O:72])[CH3:71])[CH:60]=[C:61]([N:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[CH:62]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[CH3:52][C:50]1([CH3:53])[CH2:51][N:47]([C:38]2[C:37]([CH3:55])=[C:36]([NH:56][C:57]3[CH:58]=[C:59]([NH:69][C:70](=[O:72])[CH3:71])[CH:60]=[C:61]([N:63]4[CH2:68][CH2:67][O:66][CH2:65][CH2:64]4)[CH:62]=3)[C:45]3[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=3)[N:39]=2)[C:48](=[O:54])[CH2:49]1
Reactant: Cc1c(N2CC(C)(C)CC2=O)nc2cc(F)ccc2c1Cl
Reactant: CC(=O)Nc1cc(N)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(Nc2c(C)c(N3CC(C)(C)CC3=O)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X by stirring palladium (II) acetate (0.4 mg, 1.743 μmol), XPhos (2.5 mg, 5.23 μmol), 1-(4-chloro-7-fluoro-3-methylquinolin-2-yl)-4,4-dimethylpyrrolidin-2-one (0.018 g, 0.058 mmol), N-(3-amino-5-morpholinophenyl)acetamide (0.0164 g, 0.070 mmol), potassium carbonate (0.020 g, 0.145 mmol), and tert-butanol (0.5 mL) at 110° C. for 30 minutes. Purification by reverse-phase HPLC (0-70% acetonitrile in water) afforded N-(3-((2-(4,4-dimethyl-2-oxo-1-pyrrolidinyl)-7-fluoro-3-methyl-4-quinolinyl)amino)-5-(4-morpholinyl)phenyl)acetamide as a yellow amorphous solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.79 (1H, br. s.), 7.55 (2H, d, J=9.0 Hz), 7.13 (1H, t). 6.88 (1H, br. s.), 6.39 (1H, br. s.), 6.34 (1H, br. s.), 6.06 (1H, br. s.), 3.88 (2H, br. s.), 3.70-3.81 (4H, m), 2.98-3.15 (4H, m), 2.46 (2H, s), 2.13 (3H, br. s.), 2.09 (3H, s), 1.33 (6H, s). Mass Spectrum (ESI) m/e=506.2 (M+1).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[F:42]>CS(C)=O>[Br:33][C:34]1[CH:41]=[CH:40][C:37](/[CH:38]=[CH:7]/[CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:36][C:35]=1[F:42]
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CC/C=C/c1ccc(Br)c(F)c1
Reaction time: 0.67 h
Yield: 47.4 %

Procedure:
To a solution of 3-carboxypropyltriphenylphosphonium bromide (8.6 g, 20 mmol) in DMSO (20 mL) was added solid KOt-Bu (4.49 g, 40.0 mmol) at rt. After stirring for 40 min, a solution of 4-bromo-3-fluorobenzaldehyde (3.45 g, 17.00 mmol) in DMSO was added slowly. The mixture was stirred at rt for 16 h. The reaction was quenched with water (200 mL), washed with EtOAc/hexanes (1/1). The aqueous layer was neutralized with concentrated hydrochloric acid to pH=2, extracted with EtOAc. The organic layer was concentrated. The residue was purified by silica gel column chromatography (hexanes-100% EtOAc) to give (E)-5-(4-bromo-3-fluorophenyl)pent-4-enoic acid (2.2 g, 8.06 mmol, 40% yield). LCMS (M−H)−=273.1. 1H NMR (500 HMz, chloroform-d) δ 7.47 (dd, J=8.2, 7.2 Hz, 1H), 7.12 (dd, J=9.9, 2.0 Hz, 1H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 6.41-6.36 (m, 1H), 6.29-6.22 (m, 1H), 2.58-2.56 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:25])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH:22]=[O:23])[C:16]=1[F:24].CO.[OH-].[K+]>O>[CH3:11][O:12][C:13](=[O:25])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH:22]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:23])[C:16]=1[F:24]
Reactant: COC(=O)Nc1ccc(F)c(C=O)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Into a reaction flask under nitrogen, 5-bromo-1H-pyrrolo[2,3-b]pyridine (4, 1.00 g, 5.08 mmol) is combined with (2,4-difluoro-3-formyl-phenyl)-carbamic acid methyl ester (3, 1.09 g, 5.08 mmol), 10 mL of methanol and potassium hydroxide (0.41 g, 7.31 mmol). The reaction is stirred at room temperature overnight, then diluted with 30 mL of water and extracted with 1×50 mL, then 2×30 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (5, 1.91 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)c1
Yield: 88 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 88%). MS (ESI) m/z 438 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][OH:33])=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:35]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][OH:33])=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH2:27][OH:35])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)CO)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 17) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:10][C:11]1[C:12]([C:21]([F:22])([F:23])[F:24])=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:16]=1)[NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1
Yield: 82.2 %

Procedure:
4-cyano aniline (130 mg, 1.1 mmol) and 2,4-dichloro-5-nitrobenzotrifluoride (260 mg, 1 mmol) were used as starting materials. A general synthetic method of intermediate I was employed to get 5-chloro-N-(4-cyanophenyl)-2-nitro-4-trifluoromethylaniline (I-1) (281 mg) with a yield of 82%, as a yellow solid, and with a melting point of 180-182° C.; MS m/z (%) 359.2 (M+NH4, 100). I-1 and 4″-formyl-2″,6″-dimethylphenol were coupled by Method A in Preparation Example 2. The product was dissolved in 15 mL of THF, and was reacted with (EtO)2P(O)CH2CN (1.5 mmol) and an equivalent mole of potassium t-butoxide in THF by Method C in Preparation Example 2 under stirring for about 3 h. The product obtained by conventional post-treatment was isolated and purified through medium pressure column (dichloromethane/methanol) to get Compound 1, with a melting point of 248-250° C. and a yield of 87%. 1H NMR δ ppm 2.15 (6H, s, 2×CH3), 5.85 (1H, d, J=16.4 Hz, ═CH), 6.27 (1H, s, ArH-6), 7.10 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.21 (2H, s, ArH-3″,5″), 7.32 (1H, d, J=16.4 Hz, CH═), 7.52 (2H, d, J=8.8 Hz, ArH-3′,5′), 8.67 (1H, s, ArH-3), 9.91 (1H, s, NH); MS m/z (%) 501.1 (M+Na, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].Br[C:20]([F:24])([F:23])[CH:21]=[CH2:22].Cl>CN(C)C=O>[F:23][C:20]([F:24])([CH:21]=[CH2:22])[CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: C=CC(F)(F)Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: Cl
Solvent: CN(C)C=O
Product: C=CC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of 1.0 g 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde and 868 mg 3-bromo-3,3-difluorpropene in 10 ml dimethylformamide 425 mg Indium were added and the resulting suspension was stirred in an ultrasonic bath for two hours. Then 20 ml 1 N hydrochloric acid were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 740 mg 2,2-Difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol as a colorless lyophilisate.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:30]=[C:10]3[N:11]=[C:12]([CH3:29])[C:13]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])=[C:14]([N:15]4[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH2:16]4)[N:9]3[N:8]=2)[CH:2]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:30]=[C:10]3[N:11]=[C:12]([CH3:29])[C:13]([C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[C:14]([N:15]4[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH2:20]4)[N:9]3[N:8]=2)[CH:2]=1
Reactant: COC(=O)C(=O)c1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1N1CCC(C)(C)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1N1CCC(C)(C)CC1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a stirred yellow solution of methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-(4,4-dimethylpiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (61 mg, 0.126 mmol) in anhydrous Toluene (6 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.046 mL, 0.050 mmol). The mixture was cooled to −35° C. and a solution of 1M catechoborane/THF (0.177 mL, 0.177 mmol) was added over 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. and diluted with EtOAc (100 mL) and sat. Na2CO3 (50 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×50 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by Biotage (5-70% EtOAc/hexane) to afford desired (S)-methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-(4,4-dimethylpiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (59 mg, 0.115 mmol, 92% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[C:5]([O:7][CH3:8])=[O:6].[S:18](=[O:21])([OH:20])[O-:19].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=1[CH:12]([S:18]([OH:21])(=[O:20])=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: O=S([O-])O
Reactant: COC(=O)/C=C/c1ccc(C(=O)OC)cc1Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(=O)(=O)O
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Methyl 3-bromo-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzoate (300 mg, 1.00 mmol) dissolved in ethanol (2.0 mL) was added to sodium bisulfite (209 mg, 2.00 mmol) in water (2.0 mL). The reaction mixture was heated in the microwave at 165° C. with stirring for 30 minutes. The colorless solution was purified by preparative LCMS to afford product as a white solid (0.26 g, 68%). 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J=1.5 Hz, 1H), 7.93 (dd, J=8.2, 1.8 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 5.18 (dd, J=10.0, 5.1 Hz, 1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.38 (dd, J=16.5, 5.1 Hz, 1H), 3.08 (dd, J=16.5, 10.0 Hz, 1H). LCMS found for C12H12BrO7S (M−H)−: m/z=378, 380.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[F:41][C:42]1([F:46])[CH2:45][NH:44][CH2:43]1>C(#N)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:44]4[CH2:45][C:42]([F:46])([F:41])[CH2:43]4)=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])(=[O:15])=[O:16])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: FC1(F)CNC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 396c) was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 55° C. for 48 h to give the title compound as colorless foam. MS (ESI): m/z=643.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[OH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:24]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([OH:21])[CH:23]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(B(O)O)cc1O
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: COc1ccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)cc1O
Yield: 51 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-hydroxy-4-methoxybenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(3-hydroxy-4-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (10) (1, Ar=3-hydroxy-4-methoxyphenyl) (51%), mp 265° C. (dec). 1H NMR δ [(CD3)2SO] 11.67 (s, 1H), 10.96 (s, 1H), 9.22 (s, 1H), 9.15 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.06–6.99 (m, 2H), 6.85 (d, J=8.1 Hz, 1H), 3.81 (s, 3H). EIMS found M+: 374.0900. C21H14N2O5 requires 374,0903.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][C:20](=[O:23])[NH:21][CH3:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][C:20](=[O:23])[NH:21][CH3:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CNC(=O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)CONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 84 h
Yield: 54.1 %

Procedure:
To a solution of (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[methylcarbamoylmethoxyimino-methyl]-benzamide (69.8 mg, 0.12 mmol) obtained in Step C in methylene chloride (15 ml) were added borane-pyridine complex (1994 1.92 mmol) and dichloroacetic acid (162 μl, 1.92 mmol) at room temperature, and the mixture was stirred for 3.5 days. Additional borane-pyridine complex (199 μl, 1.92 mmol) and dichloroacetic acid (162 μl, 1.92 mmol) were added, and the mixture was stirred for 1 day. The reaction mixture was diluted with methylene chloride (20 ml), and washed with saturated brine (2×20 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (EtOAc/MeOH (9:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methylcarbamoylmethoxyamino-methyl)-benzamide (36.9 mg, 53%) as a colorless oil.