Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[Cl:19][C:20]1[CH:25]=[C:24]([N+]([O-])=O)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[C:24]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:23]=[CH:22][N:21]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)c3)cc(C)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.1 g, 0.4 mmol, 1 eq.) and 2-chloro-4-nitropyridine (158 mg, 1 mmol, 2.5 eq.) in 5 ml DMF was added cesium carbonate (392 mg, 1.2 mmol, 3 eq.). The reaction was stirred at room temperature for three hours. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give desired product as light yellow oil. MS (ESI) m/z=362 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[CH:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:32]=[N:33][N:34]=[CH:35]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cnnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K68) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (79 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:18][CH:17]([O:19][CH3:20])[CH2:16]2)=[O:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([C:13]([N:15]2[CH2:18][CH:17]([O:19][CH3:20])[CH2:16]2)=[O:14])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(=O)N2CC(OC)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=O)N2CC(OC)C2)ccc1N
Yield: 98.3 %

Procedure:
A solution of (3-ethoxy-4-nitrophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 113, 230 mg, 0.821 mmol) in ethyl acetate (10 mL) was stirred with 10% palladium on charcoal under an atmosphere of hydrogen gas for 1 hour. The reaction mixture was filtered through a pad of celite, the filtrate collected and concentrated in vacuo to afford the title compound as a white solid (202 mg, 98%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1>>[CH2:8]([O:9][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCCc1ccccc1
Product: CCOC(=O)c1ccc(OCCc2ccccc2)cc1
Yield: 100.2 %

Procedure:
2-Phenylethanol (2.0 g) and ethyl 4-hydroxybenzenecarboxylate (2.7 g) were processed in the same manner as in Production Example 11-2 to obtain the entitled compound (4.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[N:36][CH:37]=1>>[Cl:38][C:35]1[N:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Clc1ccc(CBr)cn1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(Cl)nc2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 5-Bromomethyl-2-chloropyridine following the procedure of Example 478: MS (ES) m/z 519.1.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH2:26]([NH:30][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNCc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. Butylamine (0.543 mL, 5.5 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 89:10:1 chloroform/methanol/ammonium hydroxide) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.70 (s, 1H), 7.24 (br s, 1H), 4.42 (d, J=9 Hz, 2H), 3.90 (s, 3H), 3.16 (m, 2H), 2.38 (s, 3H), 1.64 (s, 2H), 1.44 (m, 9H), 1.27 (m, 2H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:22])C(Cl)(Cl)Cl)=[O:8].[CH2:23]([CH2:25][NH2:26])O.O>CS(C)=O>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[NH:16][C:17](=[O:22])[N:26]3[CH2:25][CH2:23][O:8][C:7]3([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:9]=2[CH:14]=1
Reactant: NCCO
Reactant: O=C(c1ccccn1)c1cc(Br)ccc1NC(=O)C(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Br)cc2C2(c3ccccn3)OCCN12
Yield: 57.7 %

Procedure:
To a solution of 1.27 g of 2-trichloroacetamido-5-bromophenyl 2-pyridyl ketone in 20 ml of dimethylsulfoxide was added 1.83 g of monoethanolamine, and the resultant mixture was heated in an oil bath at 100°C (bath temperature) for 3 hours. After cooling, the reaction mixture was poured into 100 ml of water and the resulting mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 0.6 g of 9-bromo-2,3,6,10b-tetrahydro-10b-(2-pyridyl)-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 241° - 242°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([N:22]([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.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.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:24])[CH3:23])[CH:17]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CN(C)c1cccc(CN)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Yield: 14.7 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), N-[3-(aminomethyl)phenyl]-N,N-dimethylamine (102 mg, 0.679 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (112 mg, 0.180 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (6 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-dimethylamino-benzylamino)-2H-phthalazin-1-one (28 mg) as a beige solid,
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[O:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C[C:23]([N:25](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:13]([N:10]1[CH2:11][CH2:12][C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:23]#[N:25])=[N:9]1)=[O:14]
Reactant: O=C(c1cccc(F)c1)N1CCC(c2cccc(Br)c2)=N1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Product: N#Cc1cccc(C2=NN(C(=O)c3cccc(F)c3)CC2)c1
Temperature: 80 °C
Yield: 76 %

Procedure:
A scintillation vial equipped with a stir bar was charged with [3-(3-bromo-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone (347 mg, 1.0 mmol), Zn(CN)2 (234 mg, 2.0 mmol), Zn dust (65 mg, 1.0 mmol) and DMA (10 mL). The mixture was degassed and then Pd(t-Bu3P)2 (51 mg, 0.1 mmol) was added. The mixture was heated at 80° C. for 4 h. LC-MS showed consumption of SM. The material was filtered through a pad of Fluorosil and the solvent was evaporated under reduced pressure. It was purified by chromatography using a 12 g silica cartridge eluting with heptane-EtOAc, gradient 30 to 100% EtOAc. Amount obtained: 225 mg, 0.76 mmol, 76% yield. LC-MS (ESI) m/e 294 (M+H). 1H NMR (CHLOROFORM-d) δ: 7.92-7.97 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.66-7.74 (m, 2H), 7.52-7.59 (m, 1H), 7.45 (td, J=8.0, 5.8 Hz, 1H), 7.20-7.30 (m, 1H), 4.32 (t, J=10.1 Hz, 2H), 3.26-3.34 (m, 2H). Step 2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[CH2:10][OH:11].C([Cu])#N.CN([CH:18]=[O:19])C.O>C(Cl)Cl>[Cl:9][C:4]1[C:3]2[CH2:10][O:11][C:18](=[O:19])[C:2]=2[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: OCc1c(Br)ccc(O)c1Cl
Reactant: CN(C)C=O
Agent: N#C[Cu]
Solvent: ClCCl
Solvent: O
Product: O=C1OCc2c1ccc(O)c2Cl
Temperature: 145 °C
Reaction time: 24 h

Procedure:
To a flask charged with 4-bromo-2-chloro-3-(hydroxymethyl)phenol (2.44 g, 10.3 mmol) and a stir bar was added CuCN (2.76 g, 30.8 mmol) and DMF (25 mL). The flask was fitted with a condenser and purged three times with Nitrogen. The solution was then heated to 145° C. for 2 hours. At that point, water (0.555 mL, 30.8 mmol) was added to the reaction via a syringe, and the reaction was kept at 100° C. for another 24 hours. The reaction was cooled to RT, diluted with DCM (100 mL), and filtered through a pad of celite to remove the solids. The filtrate was washed with saturated NH4OAc, dried over sodium sulfate, concentrated and purified by silica gel flash chromatography. 4-Chloro-5-hydroxy-2-benzofuran-1(3H)-one was collected after removal of solvents. 1H-NMR (500 MHz, CDCl3) δ ppm 9.13 (broad, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 5.23 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:17]>C(O)(C)C>[NH2:17][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(C3CC(O)C3)nc(I)c12
Temperature: 110 °C

Procedure:
In a Parr pressure reactor 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g, 0.0119 mol) was dissolved with 2.0 M ammonia in isopropyl alcohol (40 mL). The mixture was cooled to −20° C. and saturated with ammonia. The reaction was heated at 110° C. for 63 h at which point it was cooled and concentrated in vacuo. The crude product was purified using HPFC Jones 25 gram silica gel column eluting with 5-8% MeOH:CH2Cl2 to yield the title compounds; MS (ES+): m/z 330.88 (100) [MH+], 331.89 (10) [MH+]; HPLC: tR=0.48 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.55-2.76 (m, 2H) 3.06-3.22 (m, 2H) 3.32-3.50 (m, 1H) 4.51-4.69 (m, 1H) 6.15 (br. s., 2H) 7.24 (d, J=5.05 Hz, 1H) 7.39 (d, J=5.05 Hz, 1H)
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([O:11][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: Fc1ccc2ccccc2c1
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc2ccccc2c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH2:42][C@@H:43]([OH:46])[CH2:44][NH2:45])=[CH:30][CH:29]=1>>[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH2:42][C@@H:43]([OH:46])[CH2:44][NH:45][CH:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=4)(=[O:16])=[O:17])=[CH:10][CH:9]=3)[CH2:6][CH2:7]2)=[CH:30][CH:29]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c3ccccc3c12
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c6ccccc6c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamine (Berridge et al., Int. J. Radial. Appl. Instrum., 1992, 563) according to the procedure of Example 255 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 2.00–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–2.70 (m, 2 H), 3.00–3.50 (m, 3 H), 3.60–3.70 (m, 2 H), 4.10–4.25 (m, 2 H), 4.35–4.50 (m, 1 H), 5.97 (brs, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 6.80 (d, J=8.0 Hz, 2 H), 6.88 (d, J=8.0Hz, 2 H), 7.10–7.50 (m, 5 H), 7.59 (d, J=8.7 Hz, 2 H), 7.69 (d, J=8.7 Hz, 2 H), 8.22 (d, J=7.8 Hz, 1 H), 9.71 (s, 1 H), 10.40 (s, 1 H), 11.32 (s, 1 H); MS (ES) m/z: 627.9 (MH+); HRMS Calcd. for C34H38N5O5S (MH+): 628.2594. Found: 628.2593.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=S.[OH-].[K+]>O.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]#[N:10]
Reactant: NC(=S)Nc1ccccc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1ccccc1-c1ccccc1

Procedure:
A suspension of N-(2-biphenylyl)thiourea (7.8 g) in water (60 ml) was reacted with a solution of potassium hydroxide (19.15 g) in water (60 ml), lead acetate trihydrate (12.96) in water (60 ml) was added and the reaction mixture heated at 90°-95° C. for 30 minutes and filtered. The filtrate was acidified with acetic acid with cooling to yield 2-biphenylylcyanamide as a colourless solid (m.p. 85°-87° C.).
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1O)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:1]([C:5]1[CH2:13][C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1Cc2ccccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)C1=Cc2ccccc2C1
Yield: 99.8 %

Procedure:
A solution of 2-t-butyl-1-indanol (8.19 g, 43.1 mmol) and p-toluenesulfonic acid (0.200 g, 1.05 mmol) in benzene was heated under reflux for 0.5 h. Water (20 mL) was added. Aqueous layer was extracted with ether (4*50 mL). All organic layers were combined, washed with water (20 mL), brine (10 mL) and concentrated to produce 7.41 g (100 g) of 2-t-butyl-indene. 1H-NMR (CDCl3) δ 1.18 (s, 9 H), 3.30 (s, 2H), 6.45 (s, 1H), 7.02 (tdd, J=7.3, 1.4, 0.3 Hz, 1H), 7.14 (br t, J=7.5 Hz, 1H), 7.19 (br d, J=7.3 Hz, 1H), 7.31 (br d, J=7.3 Hz, 1 H). 13C-NMR (CDCl3) δ 30.44, 33.45, 37.84, 120.09, 123.42, 123.50, 123.63, 126.25, 143.11, 145.49, 150.16.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:40])[NH:30][C:31]3[C:36]\2=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:47]>>[ClH:47].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:40])[NH:30][C:31]3[C:36]\2=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(3-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([CH2:20][CH2:19][C:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:21])[CH:7]=[CH:6][C:5]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: C=CC(O)C1CCCC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(CCC(=O)C2CCCC2)cc1Cl
Temperature: 90 °C
Yield: 68.1 %

Procedure:
A mixture of 4-bromo-2-chloro-1-methanesulfonyl-benzene (1.5 g, 5.6 mmol), 1-cyclopentyl-2-propen-1-ol (0.88 g, 6.96 mmol) and sodium acetate (0.57 g, 6.9 mmol) in DMAC (20 mL) was purged with N2 for 30 mins. Palladium (II) acetate (25 mg, 0.11 mmol) was added and the mixture was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the desired product (1.2 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.56-1.85 (br m, 8H), 2.83 (m, 3H), 2.96 (t, J=7.5 Hz, 2H), 3.25 (s, 3H), 7.29 (dd, J=8.1, 1.5 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H).
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:22])[CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:31][CH3:32])[C:14](=[O:23])[C@H:13]([CH2:24][CH3:25])[N:12]2[S:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(Br)ccc3NC(=O)[C@@H]2CC)cc1
Reactant: CCI
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Product: CC[C@H]1C(=O)N(CC)c2ccc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-7-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl ethyl carbonate was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-6-bromo-1,3-diethyl-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−190° (c=0.0052 G/ML, DMSO); MS (ESI) m/z 439/441 ([M+H]+); MS (ESI) m/z 437/439 ([M−H]−); Anal. Calcd for C18H19BrN2O4S: C, 49.21; H, 4.36; N, 6.38. Found: C, 50.41; H, 5.02; N, 6.00.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]#[N:27])=[CH:22][N:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:19]=4[N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-:34].[K+].O>C(O)(C)(C)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]([NH2:27])=[O:34])=[CH:22][N:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:19]=4[N:20]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C#N)cn(-c5ccccc5)c4n3)cc2)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C(N)=O)cn(-c5ccccc5)c4n3)cc2)CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (Example 13F, 9 mg) in 1 mL of t-butanol was added potassium hydroxide (ground, 5 mg). The mixture was stirred at 85° C. for 1 hour. After cooling to rt, water was added and the precipitates were extracted into EtOAc. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to leave 2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide as a yellow solid (7.2 mg, 79%). 1H NMR (300 MHz, CDCl3) δ (ppm): 10.64 (br, 1H), 10.30 (s, 1H), 9.17 (s, 1H), 7.71 (m, 3H), 7.53 (br, 1H), 7.43 (m, 2H), 6.94 (br, 2H), 6.35 (br, 2H), 5.06 (br, 1H), 3.12 (m, 4H), 2.59 (m, 4H), 2.37 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H25N7O2: 456.51 (M+H), Found: 456.6.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].O[NH:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[NH:9].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][CH2:2][C:3]1[O:4][N:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:7]=1
Reactant: N=C(NO)c1nccs1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1nc(-c2nccs2)no1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
Chloroacetyl Chloride (5.0 mL, 44.5 mmol) was added to N-Hydroxy-thiazole-2-carboxamidine (0.50 g, 3.49 mmol) and K2CO3 (1.0 g, 7.20 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (0.18 g, 25%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].C(=[O:14])CCC.[CH2:15]=[O:16]>>[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[CH:15]([O-:14])=[O:16]
Reactant: CCCC=O
Reactant: C=O
Agent: CCC(CO)(CO)CO
Product: O=C[O-]

Procedure:
In the industrial production of trimethylolpropane, n-butyraldehyde is reacted with formaldehyde in an aqueous solution in the presence of an alkaline catalyst. After the reaction, trimethylolpropane is separated in a usual manner. Thus, after or without an evaporation, the reaction mixture is subjected to extraction with a solvent, for example ethyl acetate, amyl alcohol, methyl isobutyl ketone, hexyl alcohol, isooctyl alcohol or cyclohexanol. In this way a solution of trimethylolpropane substantially free from formate is obtained. Alternatively, water is substantially removed from the reaction mixture, whereupon the concentrate is filtered while hot to separate formate from crude trimethylolpropane.