Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([F:28])[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:18]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[F:28][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:18]=[C:13]([OH:12])[CH:14]=1
Reactant: Fc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1cc(F)cc(C=Cc2ccc(F)cc2)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3,4′-difluorostilbene (0.97 g, 3 mmol) in dry CH2Cl2 (120 ml) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water. Flash chromatography gave the 3,4′-difluoro-5-hydroxystilbene (0.60 g, 86%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.46 (m, 2H), 7.08-6.73 (m, 6H), 6.48 (dt, 1H), 4.85 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 165.05 (d), 161.78 (d), 157.06 (d), 140.43 (d), 133.06 (d), 129.40 (s), 128.45 (d), 127.25 (t), 115.95 (d), 109.42 (d), 105.91 (d), 102.60 (d); 19F NMR (CDCl3, 282 MHz) δ-31703.17 (t), −32099.92 (t); HRMS (EI+) found 232.0714 M+, calcd 232.0700 for C14H10F2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7].Cl[C:27]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH:14]([CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(OC)c(OC)c2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(OC)c(OC)c2)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(3′,4′-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 90) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(3′,4′-dimethoxybenzoyl)-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: [IH:1].[CH2:2]1[O:10][CH:3]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)C>[I:1][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][OH:10]
Reactant: I
Reactant: c1ccc(C2CO2)cc1
Solvent: CCOCC
Product: OCC(I)c1ccccc1
Temperature: 0 °C

Procedure:
A 250 ml round bottom flask was charged with 21 ml HI (55% aqueous solution) and cooled to 0° C. Via an addition funnel, 20 grams of styrene oxide in 80 ml of diethylether were added over a one hour period. Diethylether (45 ml) was added and the water phase was separated. The leftover organic solution was dried with Na2SO4 and evaporated. Thirty-eight grams of a faint yellow solid were obtained having a melting point of 71-72° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[NH:24][C:23]3=[O:31])[CH2:20][CH2:21]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.054 mmol) in dichloromethane (1 mL) was added 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (10 mg, 0.046 mmol, 1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H22N4O3: 402.1692, found 402.1695.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:27])OC3C=CC=CC=3)=[CH:12][CH:11]=2)[C:3]=1[N+:28]([O-:30])=[O:29].[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:41][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)(=[O:39])=[O:40])=[O:27])=[CH:12][CH:11]=2)[C:3]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCNC(=O)Oc3ccccc3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3[N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a stirred solution of phenyl 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethylcarbamate (step 2, 10.0 g, 24.6 mmol) and p-toluenesulfonamide (6.3 g, 36.8 mmol) in DMF (100 mL) was added sodium hydride (2.0 g, 50 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate/toluene (v/v, 2:1, 2×300 mL). The organic extracts were washed with water (100 mL) and brine (200 mL), then dried (Na2SO4). Removal of the solvent gave crude product. Recrystallization from ethyl acetate gave 9.6 g (81%) of the title compound as brown solids. The mother liquor was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.9 g (16%) of the title compound as brown solids.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:12]([C:27]([O:29][CH3:30])=[O:28])=[N:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][NH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41](=O)[O:42]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C>[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41]([N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([C:14]3[N:13]=[C:12]([C:27]([O:29][CH3:30])=[O:28])[C:11]([O:10][CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:16][CH:15]=3)[CH:26]=2)[CH2:21][CH2:22][CH2:23]1)=[O:42]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OCCOc1ccccc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1OCCOc1ccccc1
Yield: 98.2 %

Procedure:
Methyl 3-(2-phenoxyethoxy)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (27C) (81 mg, 0.2 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (127 mg, 0.4 mmol) were heated to reflux in acetonitrile (5 mL) for 24 hours. After cooling, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of PE (100%) to PE/EtOAc (4:6), to provide 114 mg (97%) of the desired product methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinate (27D). 1H NMR (300 MHz, CDCl3) δ8.12 (1H, s), 7.85 (1H, d), 7.73 (1H, m), 7.44 (3H, m), 7.29 (4H, m), 7.09 (1H, m), 6.94 (3H, m), 4.44 (2H, m), 4.37 (2H, m), 3.88 (2H, m), 3.78 (3H, m), 2.74 (2H, m), 2.00 (2H, m).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)#[N:40]>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[CH:46][C:41]([C:39]#[N:40])=[CH:42][CH:43]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(C#N)cc3)sc2N)c1N1CCC(CN)CC1
Yield: 30 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 4-cyanophenyl boronic acid gave 389 as a green solid (26 mg 30% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.01 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.3 Hz, 2H), 7.62 (s, 2H), 7.31 (s, 1H), 3.62 (s, 3H), 3.12-2.96 (m, 4H), 2.45 (d, J=5.6 Hz, 2H), 2.20-1.80 (m, 2H), 1.74 (d, J=11.6 Hz, 2H), 1.26-1.14 (m, 3H). LCMS (ES+) m/z 437 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([C:15]#[C:16][CH3:17])[CH2:11][C:12]([OH:14])=[O:13].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([C:15]#[C:16][CH3:17])[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC#CC(CC(=O)O)c1ccc(OC)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC#CC(CC(=O)O)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
3-(2-Fluoro-4-methoxy-phenyl)hex-4-ynoic acid (0.250 g, 1.12 mmol) is dissolved in DCM (5 mL) and boron tribromide (0.5 mL, 3.7 mmol) is added at −10° C. The mixture is stirred at ambient temperature for 1 hour. The solution is concentrated under reduced pressure, diluted with water, and extracted with EtOAc, dried with a drying agent, and concentrated under reduced pressure to give the title compound as a pale brown liquid (0.180 g, 76%). ESI/MS m/z 212 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.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>[Br:1][C:2]1[C:3]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[CH:22]=2)=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1I
Reactant: Cc1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: CCO
Product: Cc1cccc(-c2c(F)cccc2Br)c1
Temperature: 25 °C

Procedure:
Pd(Ph3P)4 in a 500-mL round-bottom flask under N2 atmosphere was treated sequentially with a solution of 1-bromo-3-fluoro-2-iodo-benzene (30 g, 0.1 mol) in toluene (250 mL), a solution of 2N aq Na2CO3 (200 mL) and 3-methyl phenylboronic acid in ethanol (62 mL). This mixture was heated at reflux under N2 for 12 h, then cooled to rt. The mixture was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO4, evaporated and purified by column chromatography to give 6-bromo-2-fluoro-3′-methyl-biphenyl (12 g). 1H NMR (400 MHz, CD3OD): 7.03 (m, 2H), 7.48-7.04 (m, 4H), 7.50 (d, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:34][CH2:33][N:25]2[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=3[CH:32]=[C:24]2[C:23]1=[O:35])(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[C@@H:54]([CH3:59])[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:22]2[CH2:34][CH2:33][N:25]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=4[CH:32]=[C:24]3[C:23]2=[O:35])=[CH:8][C:9]([F:21])=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[C@@H:54]([CH3:59])[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)[C@@H](C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 58.7 %

Procedure:
Following the procedures as described for compound 108f, reaction of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (74 mg) and 107e (60 mg) gave 107f as a yellow solid (60 mg, 59%). LCMS: [M+H]+ 668
Reaction SMILES: [CH3:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23](=[O:44])[NH:24][C:25]([C:27]1[S:28][C:29]([S:42][CH3:43])=[C:30]([S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=2)(=[O:34])=[O:33])[CH:31]=1)=[NH:26])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:18]([O:22][C:23](=[O:44])[NH:24][C:25]([C:27]1[S:28][C:29]([S:42][CH3:43])=[C:30]([S:32]([C:35]2[CH:36]=[C:37]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:8])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:31]=1)=[NH:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cccc(N)c1B1OC(C)(C)C(C)(C)O1
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: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Yield: 27.6 %

Procedure:
The procedure described in Example 1: step c was followed using 3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (95 mg. 0.41 mmol, Example 25: step b), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100.7 mg, 0.21 mmol, Example 27: step c), Pd(PPh3)4 (47 mg, 0.04 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Purification by preparative SiO2 TLC (33% EtOAc in hexanes) of the residue yielded the title compound (30 mg, 28%) as an off-white solid. ESI-MS (m/z): Calcd. For C24H27N3O4S3: 517.2; found: 517.8.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.C(OO)(=[O:30])C.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1)=[O:30]
Reactant: CC(=O)OO
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 104.4 %

Procedure:
At 0° C., a suspension of tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (51) (3.57 g, 9.29 mmol) in DCM (80 mL) was treated with peracetic acid (32 wt % in AcOH, 1.95 mL, 9.29 mmol) slowly dropwise. After 5-10 min, the reaction mixture became a homogeneous yellow solution, and after 20 min, it became a suspension again. After 1 h, the reaction mixture was treated with DCM (50 mL) followed by a solution of aqueous sodium thiosulfate and stirred at 0° C. for 5 min. It was then treated with a saturated solution of NaHCO3, extracted with DCM (6×50 mL), dried over MgSO4, filtered and concentrated affording tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52) (2.50 g, 9.70 mmol, 67% yield) as a light yellow crystalline solid. The crude material was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (1H, s), 9.28 (1H, s), 8.18 (1H, d, J=9.6 Hz), 7.53 (1H, s), 7.37-7.47 (2H, m), 6.89-6.95 (2H, m), 2.71 (3H, s), 1.46 (9H, s). m/z (ESI, +ve ion) 422.9 (M+Na)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([O:8][C:9]([C:11]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:12]=1[S:13][C:14]1[C:15]([CH2:28][C:29]([OH:31])=[O:30])=[CH:16][CH:17]=[C:18]([CH2:26][NH2:27])[C:19]=1[N:20]2[CH3:25])=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(Cl)Cl>[C:4]([O:8][C:9]([C:11]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:12]=1[S:13][C:14]1[C:15]([CH2:28][C:29]([O:31][CH3:3])=[O:30])=[CH:16][CH:17]=[C:18]([CH2:26][NH2:27])[C:19]=1[N:20]2[CH3:25])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: C=[N+]=[N-]
Reactant: CN1c2cccc(C(=O)OC(C)(C)C)c2Sc2c(CC(=O)O)ccc(CN)c21
Solvent: ClCCl
Product: COC(=O)Cc1ccc(CN)c2c1Sc1c(C(=O)OC(C)(C)C)cccc1N2C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
1 ml of diazomethane solution (~0.3N in diethyl ether) was added dropwise while cooling with ice to a solution of 80 mg (0.19 mmol) of (6-tert-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetic acid in 4 ml of methylene chloride. The reaction mixture was brought to room temperature, stirred for 1.5 hours and evaporated. The residue was crystallized from ethyl acetate/hexane, whereupon, after drying in a high vacuum, 72 mg (91%) of methyl (6-tert-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetate were obtained as a white solid. MS 414 (M+, 64), 358 (100), 343 (15), 314 (15), 238 (15), 57 (16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)=O)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:10][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(NC(=O)c2ccccc2-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cccc(NCc2ccccc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 48.4 %

Procedure:
A solution of borane-dimethylsulfide complex (2.0 M, 9 mL, 18 mmol) was added to a solution of biphenyl-2-carboxylic acid (3-methoxy-phenyl)-amide (3.03 g 10 mmol) in toluene (10 mL). The reaction mixture was refluxed and stirred for 42 hours. The reaction mixture was cooled to room temperature, 10% aqueous potassium carbonate (10 mL) was added, and the reaction mixture was vigorously stirred for 30 minutes. Extraction of the aqueous layer with ethyl acetate followed by concentration gave the crude product. Purification by silica gel column chromatography using 20% ethyl acetate in hexanes as the eluant afforded the pure product (1.4 g). MH+290: 1H (CDCl3) δ 3.72 (3H, s), 4.23 (2H, s), 6.07 (1H, m), 6.14 (1H, dm, J=8), 6.25 (1H, dm, J=8), 7.03 (1H, t, J=8), 7.22-7.32 (8H, m), 7.52 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:29])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[C:34](OCC)(OCC)([O:36][CH2:37][CH3:38])[CH3:35]>>[CH2:34]([O:36][CH:37]([N:1]=[C:2]1[C:12]2[C:6]([NH:7][C:8](=[O:29])[CH2:9][CH:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[N:11]=2)=[CH:5][CH:4]=[CH:3]1)[CH3:38])[CH3:35]
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3c(N)cccc3NC(=O)C2)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: CCOC(C)N=C1C=CC=C2NC(=O)CC(c3ccc(-n4c(C)nc5cnccc54)cc3)N=C21

Procedure:
A solution of the aniline from Example 14 (0.38 g, 1 mmol) and glacial acetic acid (0.5 ml) in triethyl orthoacetate (5 ml) was stirred at 25° C. for 72 hours. The product was filtered and recrystallised from toluene (60 mg, 13%).
Reaction SMILES: C(S[C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=2)[C:7](=[O:16])[C:8]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:9]=2[N:10]=1)CC.[O-:29][CH2:30][CH3:31].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:30]([O:29][C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:7](=[O:16])[C:8]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:9]=2[N:10]=1)[CH3:31]
Reactant: CCCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (535 mg) in N,N-dimethylformamide (5 ml) was added sodium ethoxide (20% ethanol solution, 0.863 ml), and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was allowed to be cooled to room temperature, saturated brine was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:28][C:27]=1[Cl:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=544.2 [M+H+].
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C[Si](C)(C)[N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1>C1CCCCC1.O1CCCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:13]2[CH2:14][CH2:15][NH:11][C:12]2=[O:16])=[CH:22][N:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C[Si](C)(C)N1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C1NCCC1Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere at a temperature of from −78° C. to −60° C., 180 ml of a 1.5 molar solution of lithium diisopropylamide (LDA) in cyclohexane are added dropwise to 31.4 g of N-trimethylsilylpyrrolid-2-one in 150 ml of tetrahydrofuran (THF) and the reaction mixture is stirred at the same temperature for a further one hour. Then, at from −78° C. to −60° C., 25.5 g of 2-chloro-5-chloromethylpyridine in 40 ml of THF are added, and the mixture is stirred for a further 16 hours at that temperature and then for a further three hours at room temperature. The reaction mixture is poured onto a mixture of ice/water and extracted with ethyl acetate, and the organic phase is separated off. The ethyl acetate phase is dried over sodium sulfate and concentrated to dryness by evaporation in vacuo. The residue is purified on silica gel using ethyl acetate/hexane (7:1) as eluant. The title compound having a melting point of 117-118° C. (compound 1.3) is obtained.