Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:18](=[O:21])[CH2:19]Cl)=[CH:13][N:12]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:11]1=[O:31])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:46][CH2:47][CH2:48][OH:49]>C(#N)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:18](=[O:21])[CH2:19][NH:46][CH2:47][CH2:48][OH:49])=[CH:13][N:12]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:11]1=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CNCCO)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a solution of {(R)-2-[5-(2-chloro-acetylamino)-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (44 mg, 0.08 mmol) in acetonitrile (2 mL) were added triethylamine(30 μl, 0.22 mmol) and 2-amino-ethanol (60 μl, 0.96 mmol) in that order. The solution was stirred at 60° C. for 4 hrs, cooled to room temperature, and washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer. The organic layer was concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 10/1) and dried in a vacuum to afford 37 mg of the compound as a colorless oil (yield 80%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOC[C@H]4C)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 36.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 248b (364 mg, 1.0 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (596 mg, 1.5 mmol), K3PO4 (424 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (73 mg, 0.10 mmol), sodium acetate (164 mg, 2.0 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 2.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 50:1) to afford 248c (250 mg, 37%) as yellow oil. MS-ESI: [M+H]+ 681.3
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1.N#N>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:10]1[C:9]([CH3:17])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)=[C:12]([C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cc(F)cc(F)c1
Temperature: 80 °C

Procedure:
A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyl trifluoromethanesulfonate (9.6 g, 26 mmol) and (3,5-difluorophenyl)boronic acid (5.0 g, 32 mmol) in toluene (100 mL) and saturated sodium bicarbonate in water (100 mL) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (1.22 g, 1.06 mmol) was added, the mixture was bubbled with N2 for 5 min. more and heated at 80° C. for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column, eluting with 0-30% ethyl acetate in hexane, to give the desired product. LCMS calculated for C15H11ClF2NO3 (M+H)+: m/z=326.0. found: 326.0.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:17]1[S:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=1.Cl>O.C1COCC1>[N:3]1([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:17]3[S:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCCCC2)ncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(N3CCCCC3)ncn2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flame dried flask under Ar was charged with sodium hydride (35 mg, 60% dispersion, 0.86 mmol) and 2 mL anhydrous THF. 6-Piperidin-1-yl-pyrimidin-4-ylamine (70 mg, 0.39 mmol) was added slowly followed after 10 minutes by the addition of 2-chloro-thiazole-5-carbonitrile (68 mg, 0.47 mmol). After 1 hour at room temperature the reaction was heated to reflux. After 4 hours, the reaction was cooled, diluted with water and adjusted to pH 7 with 1M HCl (aq). The resulting precipitate was filtered washed with water and air dried. The resulting solid triturated with ether, sonucated, filtered and washed with ether. 1H-NMR (400 MHz, DMSO-d6) 11.99 (s, 1H), 8.39 (1H, s), 8.24 (1H, s), 6.20 (1H, s), 3.57–3.54 (m, 4H), 1.64–1.53 (m, 6H). M+1=287.3. mp>250.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH:31]=[CH:30]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:29](=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Product: O=C(O)/C=C/C(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide and maleic anhydride following a procedure analogous to that described in Example 90. LC-MS Method 1 tR=1.7 min, m/z=478; 1H NMR (CDCl3) 1.60-2.20 (18H), 3.11 (m, 2H), 3.58 (s, 2H), 3.92 (br s, 4H), 4.39 (s, 2H), 5.00 (br s, 1H), 6.30-7.45 (6H).
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:36])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[N:24][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>C(#N)C>[ClH:1].[C:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:25]1[CH:26]=[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:36])[CH2:19][CH2:18][CH:17]\2[SH:20])[N:23]=[N:24]1)([OH:33])=[O:32]
Reactant: CCOC(=O)CCCCn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Agent: Cl
Solvent: CC#N
Product: O=C(O)CCCCn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Yield: 97.5 %

Procedure:
In a similar manner to that described in Example 134, (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[4-(ethoxycarbonyl)butyl]-1H-1,2,3-triazol-4-yl}methylidene)-4-sulfanylpiperidine hydrochloride (1.32 g) was treated with 3 N HCl. The crude product was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N HCl, 20/80, v/v) to afford the title compound as a colourless amorphous solid (1.22 g, yield: 97%).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:75])=[C:11]([CH:18]([C:45]2[N:46]([C:56]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:47]=[C:48]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:49]=2)[NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([N:30]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:25][CH:24]=[CH:23]3)[CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:34]([O:33][C:31]([N:30]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C:26]1[C:27]2[C:22](=[CH:21][C:20]([NH:19][CH:18]([C:45]3[N:46]([C:56]([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:47]=[C:48]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:49]=3)[C:11]3[C:10]([F:75])=[C:9]([OH:8])[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=3)=[CH:29][CH:28]=2)[CH:23]=[CH:24][N:25]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(O)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of Intermediate 123.2 (635 mg, 0.619 mmol) in 5 mL THF, was added TBAF (1 M, 0.619 mL, 0.619 mmol). The mixture was stirred at rt for 30 min, then was diluted with EtOAc. The organic phase was washed with 0.1 N HCl, water (2×) and brine; dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 75% EtOAc/hexanes) to afford 509 mg (90%) of Intermediate 123.3 as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH:11]=[N:10][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:5]=[CH:4][N:3]=1.NC1N=C(C2N(C3CN(C(OC(C)(C)C)=O)C3)C=NC=2C2C=CC(F)=CC=2)C=CN=1.N1CC(N2C(C3C=CN=C(N)N=3)=C(C3C=CC(F)=CC=3)N=C2)C1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:9]2[N:10]=[CH:11][N:12]([CH:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(N)n2)C1
Agent: CC(C)(C)OC(=O)N1CC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(N)n2)C1
Agent: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CNC2)n1
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNC2)n1

Procedure:
tert-Butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]pyrrolidine-1-carboxylate (C17) was converted to the product using the same conditions employed for transformation of tert-butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]azetidine-1-carboxylate (C4) to 4-[1-azetidin-3-yl-4-(4-fluorophenyl)-1H-imidazol-5-yl]pyrimidin-2-amine (C5) in Example 1. The product was obtained as a solid. Yield: 3.3 g, 10 mmol, 69%. LCMS m/z 325.6 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.09-2.18 (m, 1H), 2.32-2.41 (m, 1H), 2.98-3.11 (m, 2H), 3.16-3.23 (m, 1H), 3.3 (m, 1H, assumed; obscured by solvent signal), 5.26 (m, 1H), 6.42 (d, J=5.1 Hz, 1H), 7.07 (dd, J=8.8, 8.8 Hz, 2H), 7.42 (dd, J=8.7, 5.4 Hz, 2H), 8.05 (s, 1H), 8.14 (d, J=5.3 Hz, 1H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:4][CH2:3][CH2:2][NH:1][CH2:5][CH2:6][OH:7])=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCNCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCNCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a solution of diethanolamine (1.097 g, 10.43 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.216 g, 56%). Mass (m/z): 385.2 (M++1), 383.1 (M+−1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[O:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 88.3 %

Procedure:
A mixture of 29.4 g (0.200 mol) of 2-fluoronitrobenzene, 41.0 g (0.200 mol) of 2-chloro-4-trifluoromethylphenol and 30.0 g (0.220 mol) of K2CO3 in 150 ml of DMSO was heated at 100° C. for six hours. The reaction mixture was poured over ice and extracted with ether. The organic phase was washed with water and saturated aqueous NaCl and dried (MgSO4). The solvent was removed by evaporation at reduced pressure to yield 56.1 g (88%) of the desired product as a yellow oil. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[C:6]=1[OH:20])=[S:4].[BH4-].[Na+]>CO>[CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:19])[CH:6]1[OH:20])=[S:4]
Reactant: CNC(=S)C1=C(O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(C)C1O
Yield: 28.6 %

Procedure:
To a mixture of 2.08 g of N-methyl-6-nitro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide and 50 ml of methanol was added 1.33 g of sodium borohydride at -10° C. while stirring. The mixture was stirred for 24 hours while slowly raising the temperature from -10° C. up to room temperature, followed by concentration under reduced pressure. Water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of methylene chloride and n-hexane to obtain 0.6 g of N-methyl-6-nitro-3,4-dihydro-3-hydroxy-2,2-dimethyl -2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Yield: 37 %

Procedure:
A solution of 2-amino-5-bromopyridine (9.46 g, 20 mmol) and N,N-diisopropylethylamine (3.10 g) in chloroform (20 ml) was added to a solution of methyl chloroformate (2.30 g, 24 mmol) in chloroform (25 ml) dropwise with stirring at 0° C. The reaction mixture was stirred for 20 minutes, filtered and the precipitate was washed with chloroform and dried to afford 1.71 g (37%) of the title product as a white solid. mp 191-192° C. 1H NMR (CDCl3): δ=8.42 (d, 1 H); 8.30 (d, 1 H); 7.91 (d, 1 H); 7.77 (d of d, 1 H); 3.79 (s, 3 H). MS (EI): m/z=230, 232 (M+, Br isotopes).
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)[N:4]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH3:35])([CH3:34])[C:26]1=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1>CCOCC.O>[Cl:11][C:9]([Cl:12])([Cl:10])[C:7]1[N:8]=[C:3]([C:2]([Cl:1])([Cl:22])[Cl:23])[N:4]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([CH:36]=[C:26]3[C:27]([CH3:34])([CH3:35])[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]3[CH3:24])=[O:18])=[CH:15][CH:14]=2)[N:6]=1
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1C(=CC(=O)c2ccc(-c3nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n3)cc2)C(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(4,6-Bis-trichloromethyl-s-triazin-2-yl)benzoylchloride (15.4 pbw) are added dropwise with stirring at 10° C. to 5.2 pbw of 1,3,3-trimethyl-2-methylene-indoline and 10.6 pbw of triethylamine in 140 pbw of anhydrous toluene. The mixture is stirred for 3 hours at room temperature. It is then admixed with 100 pbw of water and 200 pbw of ether and extracted by shaking. The dried organic phase is concentrated. The residue is recrystallized from 2-methoxy-ethanol, giving red-orange crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NCc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C)(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)-2-methylpropanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 405 (M+H)+; MS (ESI−) m/z 403 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (s, 3H), 1.64 (s, 3H), 4.33 (d, J 6.1, 2H), 6.57 (s, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.52 (m, 2H), 7.82 (m, 1H), 8.11 (m, 1H), 8.36 (d, J 7.8, 1H), 8.57 (m, 1H), 9.42 (s, 1H), 10.08 (s, 1H); Anal. Calcd for C21H19F3N2OS+2HCl: C, 52.84; H, 4.43. Found: C, 52.66; H, 4.39.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:15]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl.O>[NH:1]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH2:15]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc2ccccc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-amino-2-naphthoic acid (15 g, 66.8 mmol) in conc. HCl (100 ml) and water (100 ml) at 0° C. was added NaNO2 (9.22 g, 69 mmol) in 1 g portions while maintaing the reaction temperature below 0° C. After 30 min below 0° C., SnCl2.H2O (75 g) was added in portions over 20 min. The ice bath was removed and stirred at ambient temperature for 1 h. Reaction was filtered and the filter cake washed with water and air dried. The crude material containing tin (II) salts was used as is and gave a mp>300° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[CH2:7](Br)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:10]1(/[CH:9]=[CH:8]/[CH2:7][O:5][CH2:4][CH2:3][OH:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCC=Cc1ccccc1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOC/C=C/c1ccccc1
Yield: 40.5 %

Procedure:
8 Milliliters of 85% sodium hydroxide aqueous solution mixed with 46 g of ethylene glycol was heated at 40°-50° C., and 15 g of cinnamyl bromide was added dropwise thereto. After the addition was finished, the reaction mixture was heated at 100°-110° C. for 2 hours. The reaction mixture was allowed to cool, and poured into 50 ml of water, then extracted with ether. The ether extract was washed with water and a saturated aqueous solution of sodium chloride in this order, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: chloroform) to yield 5.5 g of 2-[3-phenyl- 2(E)-propenyloxy]ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CCCCCC.[I:29]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[C:16]([I:29])=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: Cc1cccc(C(=O)Nc2cccc(Cl)c2)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(I)c(C(=O)Nc2cccc(Cl)c2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of 6-Methyl-pyridine-2-carboxylic acid-(3-chloro-phenyl)-amide (1.96 g, 7.9 mmol) in THF (20.0 ml) was cooled to −78° C. A 1.6 M solution of n-BuLi in hexane (11.0 ml, 17.6 mmol, 2.2 equiv.) was added dropwise and the reaction was stirred for 30 min at −78° C. A solution of 2.02 g (7.9 mmol) of iodine in THF (20.0 ml) was added dropwise maintaining the temperature below −75° C. After 5 min, the reaction mixture was allowed to warm up to r.t. The mixture was quenched by the addition of sat. ammonium sulfate soln. (5 ml) and 40% sodium hydrogensulfite solution (5 ml). The pH of the solution was adjusted to 8 by the addition of sat. bicarbonate soln. The mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vaccuo. The dark brown residue (2.66 g) was purified by flash chromatography (heptane/ethyl acetate 9:1) to yield a the title compound as a beige solid (total 1.42 g, 48%), MS (ISP): m/e=373.0, 375.0 (M+H+).