Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:9])[C:4](=[O:29])O1.[CH2:31]=O.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CO>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:10]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:8]([C:7]2[CH2:31][N:33]([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:4](=[O:29])[C:5]=2[OH:6])=[O:9])=[CH:27][CH:26]=1
Reactant: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)OCCCN2CCOCC2)O1
Reactant: C=O
Reactant: NCCN1CCOCC1
Solvent: CO
Product: O=C1C(O)=C(C(=O)N(Cc2ccc(F)cc2)OCCCN2CCOCC2)CN1CCN1CCOCC1
Yield: 20 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.080 g, 0.19 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.019 g (20% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.65 (2H, m, CH2), 2.25 (2H, t, J=7.3 Hz, NCH2), 2.29 (4H, broad, 2×NCH2), 2.39 (4H, broad, 2×NCH2), 2.46 (2H, t, J=6.6 Hz, CH2), 3.50 (2H, t, J=6.6 Hz, NCH2), 3.68 (8H, broad, 4×OCH2), 3.84 (2H, t, J=7.0 Hz, OCH2), 4.11 (2H, s, NCH2), 4.87 (2H, s, NCH2), 7.16 (2H, m, aromatics), 7.40 (2H, m, aromatics). HRMS (MAB N2) calculated for C25H35FN4O6: [M]+: 506.254064; found: 506.254892.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[S:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Br[C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25].Cl>CN(C)C=O>[C:24]([C:23]([CH3:28])([S:17][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:27])([OH:26])=[O:25]
Reactant: [H][H]
Reactant: CC(C)(Br)C(=O)O
Reactant: S=c1[nH]c2ccccc2cc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Sc1nc2ccccc2cc1-c1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
3-Phenylquinolin-2-thione (1.18 g.) was added to a suspension of sodium hydride (0.46 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (10 ml.) at 0°-5°. When all the hydrogen had evolved, 2-bromoisobutyric acid (0.88 g.) was added and the mixture was heated at 80° for 16 hr. The mixture was cooled to ambient temperature, poured into ice-water (50 ml.), acidified to pH 2 with concentrated hydrochloric acid, and extracted with ethyl acetate (3×25 ml.). The ethyl acetate extract was washed with brine (25 ml.) and then dried (MgSO4). The solvent was evaporated and the residual oil was chromatographed on silica (100 g., Merck type 7734), eluted with increasing concentrations of ethyl acetate in petroleum ether. The eluate obtained with 10% v/v ethyl acetate in petroleum ether was evaporated and the solid residue crystallised from cyclohexane to give 2-(1-carboxy-1-methylethylthio)-3-phenylquinoline, m.p. 144°-6°.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH2:8]1[O:10][C@H:9]1[CH2:11]Cl.CC(C)([O-:16])C.[K+]>C(O)(C)(C)C>[CH2:11]([O:7][CH2:1][CH:6]1[O:16][CH2:5]1)[CH:9]1[O:10][CH2:8]1
Reactant: ClC[C@H]1CO1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccccc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: C(OCC1CO1)C1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 139.1 %

Procedure:
The starting phenol derivative (13 g) of the following formula: ##STR35## and the same R-(-)-epichlorohydrin (13.2 g) as used in Preparation 3, potassium t-butoxide (8.8 g) and t-butyl alcohol (80 ml) are mixed and stirred at 60° C. for 2 hours. After the reaction mixture is concentrated, chloroform is added to the concentrate and the resultant is washed with a saturated saline solution and dried over anhydrous magnesium sulfate. Chloroform is distilled away under reduced pressure to give a crude product. The crude product is purified by silica gel column chromatography to give S isomer of a glycidyl ether (14.2 g) of the following formula: ##STR36##
Reaction SMILES: [CH2:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:5]=1[CH2:6][CH:7]1[CH2:11][C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]12)[CH:2]=[CH2:3].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:5]=1[CH2:6][CH:7]1[CH:8]2[N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C:10](=[O:12])/[C:11]/1=[CH:29]\[N:30]([CH3:32])[CH3:31])[CH:2]=[CH2:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: C=CCc1cccc2c1CC1CC(=O)N(C(=O)OC(C)(C)C)C21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1cccc2c1CC1/C(=C/N(C)C)C(=O)N(C(=O)OC(C)(C)C)C21
Yield: 93 %

Procedure:
A solution of the tert-butyl 5-allyl-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Step 4, 0.21 g, 0.7 mmol) in tert-butoxybis(dimethylamino)methane (0.415 mL, 2.0 mmol) in toluene (3 ml) was heated at 110° C. overnight. The solution was diluted with ethyl acetate and washed twice with water, brine, dried over magnesium sulphate and concentrated to give tert-butyl (3Z)-5-allyl-3-(dimethylaminomethylene)-2-oxo-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate D1 (colourless solid, 0.24 g, 97%). This compound was used without extra purification. LC-MS (Method C) RT 1.05 min, 369 (M+H+). This method was used to prepare compound D2 to D13 (table D).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.C(O)C.Cl.[O:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1>O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:34][C:31]3[CH:30]=[CH:29][C:28]([C:27]4[O:23][CH:24]=[N:25][CH:26]=4)=[CH:33][CH:32]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(-c2cnco2)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(-c3cnco3)cc2)nc(N)n1
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a mixture of 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (100 mg, 0.37 mmol) and ethanol (20 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.1 ml). After stirring for 10 minutes, 4-oxazol-5-yl-phenyl-amine (60 mg, 0.37 mmol) was added and the mixture was heated under reflux for 5 hours. After concentrating under reduced pressure, the residue was stirred with ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The solid was filtered and purified by flash chromatography eluting with ethyl acetate-hexane (1:1 followed by 3:2) to yield the title compound (110 mg, 75% yield). 1H NMR (acetone-d6) δ 1.44 (t, 3H, J=7.0 Hz, CH3), 4.17 (q, 2H, J=7.0 Hz, CH2), 5.88 (br s, 2H, NH), 7.04 (s, 1H, Ar), 7.12 (d, 1H, J=8.5 Hz, Ar), 7.37 (dd, 1H, J=8.8 Hz, J=2.9 Hz, Ar), 7.46 (s, 1H, Ar), 7.68 (d, 2H, J=8.7 Hz, Ar), 7.88-7.91 (m, 2H, Ar), 8.07 (d, 1H, J=2.8 Hz, Ar), 8.16 (s, 1H, Ar), 8.64 (br s, 1H, NH).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.CN.CO[C:16]1[C:20]([NH:21][CH3:22])=[N:19][S:18](=[O:24])(=[O:23])[N:17]=1.[NH:25]([C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH2:38])[N:33]=1)[C:26]([NH2:28])=[NH:27]>>[NH:25]([C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH:38][C:16]2[C:20]([NH:21][CH3:22])=[N:19][S:18](=[O:24])(=[O:23])[N:17]=2)[N:33]=1)[C:26]([NH2:28])=[NH:27]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CNC1=NS(=O)(=O)N=C1OC
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with one equivalent of methylamine and treatment of the resultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine yields the title compound, which is identical to the product obtained in Example 31.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[OH:39]>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[O:18])=[O:7])=[C:28]([CH3:35])[CH:27]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Reactant: NCC(O)c1ccc(O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc(O)cc2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 90% purity by HPLC. MS(ESI+): m/z=502.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)cc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (92 mg, 0.25 mmol) and 4-ethynyl-benzenesulfonamide (45 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (52 mg, 49%). MS (ISP) 423.3 [(M+H)+]; mp 230–233° C.
Reaction SMILES: [ClH:1].N[N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[CH:13]1([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1>>[ClH:1].[CH:13]1([N:16]2[CH2:21][CH2:20][C:19]3[N:3]4[C:8]5[C:9](=[CH:10][CH:11]=[CH:12][C:7]=5[O:6][CH2:5][CH2:4]4)[C:18]=3[CH2:17]2)[CH2:15][CH2:14]1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: NN1CCOc2ccccc21
Agent: Cl
Product: c1cc2c3c(c1)c1c(n3CCO2)CCN(C2CC2)C1

Procedure:
4-Amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride is reacted with 1-cyclopropyl-4-piperidone according to the procedure of Example 110 to yield the title compound, m.p. 232°-233° .
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])([C:11]1[N:12](COC)[CH:13]=[CH:14][N:15]=1)[OH:10].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])([C:11]1[NH:15][CH:14]=[CH:13][N:12]=1)[OH:10]
Reactant: COCn1ccnc1C(O)(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: OC(c1ncc[nH]1)(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl

Procedure:
A solution of 10 g (0.023 mol) of α,α-bis(2,4-dichlorophenyl)-1-(methoxymethyl)imidazole-2-methanol in 150 ml. of glacial acetic acid, 15 ml. of concentrated hydrochloric acid and 15 ml. of water was refluxed for two hours and then concentrated. The residue was dissolved in a small amount of a mixture of ethanol and 2N hydrochloric acid and the solution was extracted with diethyl ether. The extract was dried over sodium sulphate and the ether was distilled off. Diethyl ether and petroleum ether (boiling range 60°-80° C.) were added, the solid substance was filtered off and twice crystallised from isopropyl alcohol with a little ethanol. α,α-Bis(2,4-dichlorophenyl)imidazole-2-methanol was obtained. Melting point 193° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[O:26][C:27]=2[CH3:28])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:25]1[O:26][C:27]([CH3:28])=[C:23]([CH2:22][O:21][C:18]2[N:19]=[CH:20][C:15]([CH2:14][O:1][C:2]3[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=3)=[CH:16][CH:17]=2)[N:24]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (533 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethoxy]-1-methyl-1H-pyrazol-4-yl]acetate (623 mg, yield 81%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[CH:13][N:14]=2)[N:11]=1)=[O:4].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([N:12]=[CH:13][N:14]=4)[N:11]=3)=[O:4])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CBr)Nc1ccc2ncnn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
2-Bromo-N-([1,2,4]triazolo[1,5-b]pyridazin-6-yl)acetamide (636 mg) and 1-(diphenylmethyl)piperazine (627 mg) were dissolved in acetonitrile (20 ml), followed by addition of potassium carbonate (411 mg). The mixture was stirred at room temperature for 2 hours, followed by addition of ice-water and extraction with ethyl acetate. The extract was washed with aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals were collected by filtration and recrystallized from methanol to yield the title compound (525 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[N:13][CH:14]=1.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>N1C=CC=CC=1.CCOC(C)=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH:12]=[N:13][CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NCCc1cncc(-c2cccc(Cl)c2Cl)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCCc1cncc(-c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a solution of 2-(5-(2,3-dichlorophenyl)pyridin-3-yl)ethanamine (35 mg, 0.131 mmol) in pyridine (3 ml) at 0° C. was added ethanesulfonyl chloride (0.037 ml, 0.393 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification via PTLC (eluent; 60% EtOAc/Heptane, v/v) gave N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)ethyl)ethanesulfonamide (8.1 mg, 0.023 mmol, 17% yield).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[K].O.O1CCO[CH2:40][CH2:39]1>C(Cl)Cl>[CH2:39]([C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2)[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1COC1CCCCO1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a suspension of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (200 mg, 0.46 mmol), cesium carbonate (601 mg, 1.8 mmol), potassium ethylrifluoroborate (125 mg, 0.92 mmol) in dioxane (3 mL)/H2O (0.3 mL) Pd(OAc)2 (21 mg, 0.092 mmol) and Ru-Phos (CAS 787618-22-8, 86 mg, 0.18 mmol) were added and then the mixture was stirred at 90° C. for 15 h. The reaction mixture was cooled to room temperature, and diluted with CH2Cl2. The organic phase was separated and washed with H2O, and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue that was purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 3/2) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.75 (d, J=3.79 Hz, 1H), 7.57 (d, J=8.34 Hz, 2H), 7.31 (d, J=8.34 Hz, 2H), 6.95 (s, 1H), 6.91 (d, J=3.79 Hz, 1H), 4.90 (d, J=11.24 Hz, 1H), 4.65 (d, J=11.24 Hz, 1H), 4.61-4.64 (m, 1H), 3.79-3.92 (m, 1H), 3.41-3.54 (m, 1H), 2.71 (q, J=7.58 Hz, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 1.56-1.75 (m, 2H), 1.38-1.56 (m, 4H), 1.16 (t, J=7.58 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]([CH2:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](S(CC[Si](C)(C)C)(=O)=O)N=C4)[C:22]([OH:24])=[O:23])=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:44].[Li+].CO.[O:48]1[CH2:52]CCC1.O>>[O:44]=[C:52]1[NH:31][C:32]2[CH:33]=[CH:34][C:26]([CH2:25][C@@H:21]([NH:20][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([N:11]4[CH2:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]4=[O:1])[CH2:13][CH2:14]3)=[O:19])[C:22]([OH:24])=[O:23])=[CH:27][C:28]=2[O:48]1
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)O)ccc21
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
Prepared as described above for (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid. The hydrolysis conditions (lithium hydroxide/methanol-tetrahydrofuran-water (1:1:1) at −15° C. overnight were used. The title compound was obtained as a white solid (95%). Mass spec.: 480.30 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[C:14]([S@@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6](/[C:8](=[N:20]/[S:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])/[CH:9]([F:11])[F:10])[CH:7]=1
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)/N=C(/c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To the mixture of 1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (6.0 kg, 23.7 mol) and (S)-(−)-tert-butanesulfinamide (3.3 kg, 27.2 mol) were added toluene (73 L) with stirring at ambient temperature. After 5 min, titanium ethoxide (6.5 kg, 28.5 mol) was added and the mixture was heated to 50˜55° C. The mixture was stirred at 50˜55° C. for 3 h and allowed to cool to ambient temperature before concentration in vacuo. The resulting crude product was used directly in next chemical transformation without further purification. ESIMS: 356 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:25][CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:4][N:3]=[C:2]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH2:27][CH2:28]2)=[CH:7][CH:8]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(4-methoxyphenyl)phthalazine described in 3.4 with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([O:6][C:7]2[S:11][N:10]=[C:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:8]=2[C:20]#[N:21])=[C:4]([CH3:25])[CH:3]=1.CO[CH:28](OC)[N:29]([CH3:32])[CH2:30][CH3:31]>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:9]2[C:8]([C:20]#[N:21])=[C:7]([O:6][C:5]3[C:4]([CH3:25])=[CH:3][C:2]([N:1]=[CH:28][N:29]([CH2:30][CH3:31])[CH3:32])=[C:23]([CH3:24])[CH:22]=3)[S:11][N:10]=2)=[CH:18][CH:17]=1
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(Oc2snc(Cc3ccc(Cl)cc3)c2C#N)c(C)cc1N
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2snc(Cc3ccc(Cl)cc3)c2C#N)cc1C
Reaction time: 22 h

Procedure:
A solution of 1.80 g (4.87 mmol) of 5-(4-amino-2,5-dimethylphenoxy)-3-(4-chlorobenzyl)isothiazole-4-carbonitrile and 0.91 g (6.8 mmol) of N-(dimethoxymethyl)-N-methylethanamine in 60 ml of toluene is stirred at 80° C. for 22 h. Another 0.91 g (6.8 mmol) of N-(dimethoxymethyl)-N-methylethanamine is added, and the solution is then stirred for a further 22 h.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1F)#[N:2].[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.[H-].[Na+]>CN(C)C=O.O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(-n2cccn2)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Methyl 4-cyano-3-fluorobenzoate (0.30 g) and 1H-pyrazole (0.14 g) were dissolved in N,N-dimethylformamide (10 ml). To the reaction solution, sodium hydride (0.10 g) was added under ice cooling while stirring the mixture, and the mixture was stirred for 30 min. After increasing the temperature to room temperature, the solution was further stirred for 2 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then purified by column chromatography to give methyl 4-cyano-3-(1H-pyrazol-1-yl)benzoate (0.28 g, yield 73%).