Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:19][CH3:20])[S:12][C:13]([C:14]([O:16]CC)=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:19][CH3:20])[S:12][C:13]([C:14]([OH:16])=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1nc(C)oc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=O)O)c2c1-c1oc(C)nc1CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylate (1.88 g) was suspended in a mixed solvent of ethanol (15 ml) and tetrahydrofuran (10 ml); a 2 N aqueous solution of sodium hydroxide (9.1 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 2 hours, the solution obtained was poured over water (300 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylic acid (1.61 g, 94.2%), which was then recrystallized from chloroform-methanol. Light-yellow prisms. Melting point over 300° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[N:15]1[CH2:24][C:23]2[C:18](=[N:19][C:20]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33](OCC)=[O:34])=[CH:28][CH:27]=3)=[N:21][CH:22]=2)[N:17]([CH3:38])[C:16]1=[O:39]>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[N:15]1[CH2:24][C:23]2[C:18](=[N:19][C:20]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][OH:34])=[CH:28][CH:27]=3)=[N:21][CH:22]=2)[N:17]([CH3:38])[C:16]1=[O:39]
Reactant: CCOC(=O)Cc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3ccc(CCO)cc3)nc21
Reaction time: 1.5 h
Yield: 68.6 %

Procedure:
A 1.0M solution of lithium aluminium hydride in anhydrous tetrahydrofuran (91 μl; 91 μmol) was added dropwise to a stirred solution of 40 mg (82 μmol) of ethyl 2-[4-[[3-(2,6-dichlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxopyrimido[4,5-d]pyrimidin-7-yl]amino]-phenyl]acetate in 4 ml of anhydrous tetrahydrofuran at 0° C. and the mixture was stirred for a further 90 minutes. The reaction was quenched with 10 ml of 2M sodium hydroxide and the mixture was extracted twice with 10 ml of ethyl acetate each time. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (2:1) for the elution. Product-containing fractions were evaporated to give 25 mg (68%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-[4-(2-hydroxyethyl)anilino]-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 148-151° C.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C@H:5]1[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:16]([O:17][CH2:18][CH:19]=[CH2:20])[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:46]([O:53][C@H:54]1[C@H:67]([O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:66]([CH2:76][O:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[O:65][C@H:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C@H:55]1[OH:85])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CCN(CC)CC>ClCCCl>[CH2:18]([O:17][C@H:16]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:32][C@H:5]([O:85][C@H:55]2[C@@H:54]([O:53][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:67]([O:68][CH2:69][C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[C@@H:66]([CH2:76][O:77][CH2:78][C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)[O:65][C@@H:56]2[O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:19]=[CH2:20]
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 3-O-allyl-2,4,6-tri-O-benzoyl-α-D-mannopyranosyl trichloroacetimidate [26] (902 mg, 1.21 mmol) and benzyl 3,4,6-tri-O-benzyl-α-D-mannopyranoside [27] (723 mg, 1.34 mmol) in 1,2-DCE (10 mL), was stirred in the presence of mol. sieves (1.0 g of 3 Å powder) under an atmosphere of argon (30 min). The mixture was cooled (0° C.) with continued stirring (10 min) prior to the addition of TMSOTf (219 μL, 1.21 mmol). After some time (10 min), Et3N (100 μL) was introduced and the mixture was filtered. The solvent was evaporated and the residue subjected to FC (10-50% EtOAc/hexane) to yield the tribenzoate (24) as, a colourless oil (1.14 g, 84%). 1H NMR (CDCl3) δ 3.67-3.81, 3.88-3.95, 4.06-4.15, 4.30-4.35 (4 m, 12H; H-2I,-3I,-4I,-5I,-6aI,-6bI,-3II,-5II,-6aII,-6bII, OCH2), 4.94-4.70 (m, 7H; CH2Ph), 4.84 (d, 1H, JA,B 10.8 Hz; A of AB quartet), 4.93-4.96, 5.04-5.09 (2 m, 2H; ═CH2), 5.02 (d, 1H, J1,2 1.9 Hz; H-1I), 5.24 (d, 1H; J1,2 1.9 Ha; H-1II), 5.59-5.69 (m, 1H; ═CH), 5.72 (dd, 1H, J2,3 3.1 Hz; H-2II), 5.75 (dd, 1H, J3,4 9.8, J4,5 9.9 Hz; H-4II), 7.09-7.58, 7.97-8.06 (2 m, 35H; Ar). 13C NMR (CDCl3) δ 61.50, 63.49 (2 C; C-6I,-6II), 68.63, 69.17, 69.31, 69.46, 69.64, 71.08, 72.04, 72.64, 73.60, 74.73, 75.30, 75.38 (13 C; C-3I,-4I,-5I,-2II,-3II,-4II,-5II, OCH2, CH2Ph), 79.97 (C-2I), 98.52, 99.60 (C-1I,-1II), 117.67 (═CH2), 127.70-138.43 (43 C; ═CH, Ar), 165.61, 165.69, 166.42 (3 C; C═O).
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)[N:10]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)[N:10]=1
Reactant: COCc1nc(Cn2ncc([N+](=O)[O-])n2)co1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1nc(Cn2ncc(N)n2)co1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(methoxymethyl)-4-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)oxazole (21 mg, 0.09 mmol), iron powder (15 mg, 0.26 mmol) and NH4Cl (24 mg, 0.44 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (5 mL) was added followed by 1N NaOH (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2×5 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.41 min; [M+H]+=210.22.
Reaction SMILES: Cl.[C:2](#[N:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:9]([O:10]C)=[C:6]([O:7]C)[CH:5]=1>N1C=CC=CC=1>[OH:10][C:9]1[C:6]([OH:7])=[CH:5][C:4]([CH2:3][C:2]#[N:14])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC#N)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: N#CCc1ccc(O)c(O)c1
Temperature: 170 °C

Procedure:
Hydrogen chloride gas is bubbled through a suspension of 2 moles (354 g) of homoveratronitrile in 161 ml of pyridine, with stirring and under a nitrogen atmosphere. As soon as the temperature reaches 115° C. and becomes stable, the bubbling is discontinued; the reaction medium is heated to 170° C. for 3 hours. During this period, hydrogen chloride is bubbled through for 5 to 10 minutes at approximately half-hourly intervals. When the reaction has ended, the reaction mixture is poured into a mixture of ice and water (1.2 kg).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][C:9]([CH2:11][O:12][C:13](=[O:53])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]3[C@H:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[F:35])[C@:26]([C:38]4[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=4[F:45])([C:36]#[N:37])[C@H:25]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:24]3)=[O:22])=[C:16]([O:51][CH3:52])[CH:15]=2)=[O:10])[CH2:4][O:3]1.CO.FC(F)(F)C(O)=O>O.C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]([CH2:11][O:12][C:13](=[O:53])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]2[C@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])[C@:26]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@H:25]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:24]2)=[O:22])=[C:16]([O:51][CH3:52])[CH:15]=1)=[O:10]
Reactant: COc1cc(C(=O)OCC(=O)NCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)OCC(=O)NCC(O)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.2 %

Procedure:
In a 4 dram vial, 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methylamino)-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 67, 67 mg, 85.1 μmol) was combined with methanol (1 mL), methylene chloride (0.5 mL) and water (2 drops) to give a colorless solution. Trifluoroacetic acid (19.4 mg, 13.1 μL, 170 μmol) was added. The reaction mixture was stirred at room temperature for 5 h then concentrated. The residue was reconstituted with methylene chloride (100 mL). It was washed with saturated aqueous sodium carbonate solution, then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude residuw was purified by flash chromatography (23 g SUPELCO spherical silica gel column, eluted with methanol in ethyl acetate) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2,3-dihydroxy-propylcarbamoyl)-methyl ester (23 mg, 36% yield). LCMS (ES+) m/z calcd. for C36H39Cl2F2N4O7 [(M+H)+]: 747. found: 747.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:38])[CH:35]([CH3:37])[CH3:36])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:38][CH:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(CCCCC(O)C(C)C)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(O)CCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.1 ml of concentrated sulphuric acid in 1 ml of methanol with 60 mg (0.13 mmol) of 7-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methylheptan-3-ol in 1 ml of methanol and 1 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), a yellowish oil (m=7 mg; Y=16%) is obtained.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[NH:14]1[CH2:18][CH2:17][C@@H:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:18][CH2:17][C@@H:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:15]3)[S:3][C:4]=2[CH:10]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Temperature: 100 °C

Procedure:
A stirred mixture of 2-chloro-6-bromobenzothiazole (2.48 g, 10.0 mmol), (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 2.73 g, 0.0120 mole), and potassium carbonate (6.00 g, 0.04438 mole) in N,N-dimethylformamide (15 mL) was heated to 100° C. with an oil bath for 15 hours. The reaction mixture was cooled to room temperature then poured into water (300 mL). The resulting precipitate was collected by filtration and the filter cake was rinsed with water (600 mL). The solid was dissolved in dichloromethane and the solution was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a solid that was crystallized from hot ethyl acetate to give (R)-6-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.46-1.55 (m, 2H), 1.65 (pentet, J=5 Hz, 4H), 1.92-2.07 (m, 1H), 2.29-2.39 (m, 1H), 2.43-2.64 (m, 4H), 3.00-3.12 (m, 1H), 3.33-3.41 (m, 1H), 3.46-3.57 (m, 1H), 3.66-3.75 (m, 1H), 3.77-3.86 (m, 1H), 4.07-4.35 (m, 4H), 7.35 (d, J=9 Hz, 1H), 7.40 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].Cl.[NH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>>[C:25]([O:24][C:22]([NH:21][C@@H:16]([CH2:15][NH:14][C:10](=[O:12])[CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reactant: O=Cc1cnc(NCC(=O)O)s1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@H](CNC(=O)CNc1ncc(C=O)s1)NC(=O)OC(C)(C)C
Yield: 41.5 %

Procedure:
Following the general procedure as described in Example 24, except using 2-((5-formylthiazol-2-yl)amino)acetic acid, 1.00 HCl (150 mg, 0.674 mmol), (S)-methyl 3-amino-2-((tert-butoxycarbonyl)amino)propanoate (see U.S. Publication No. 2007/93414 A1, 164 mg, 0.751 mmol), -1-hydroxy-7-azabenzotriazole (45 mg, 0.331 mmol), CH2C2 (5 mL), N-methylmorpholine (128 μL, 1.164 mmol), EDC (128 mg, 0.667 mmol) and stirring at room temp for 1 h, 108 mg (41.5%) of the title compound is isolated as an orange/red solid. Purification is done by BIOTAGE® Silica gel chromatography on a 20 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc over 10 column volumes. LC/MS (Condition A): ret. T=2.54 min, (M+Na) 409.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](Cl)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28]([O-:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].CN(C)C=O>O>[C:22]1([S:28]([CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of methyl 3-(4-benzyloxyphenyl)-2-chloropropanoate (International Patent Appl., Publication No. WO 9101337) (0.50 g), sodium benzenesulphinate (0.29 g) and dry N,N-dimethylformamide (25 mL) was heated at 80° C. for 24 hrs. The mixture was cooled and diluted with water (500 mL), then extracted with dichloromethane (2×250 mL). The combined organic solutions were washed with water (2×250 mL) and brine (250 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with dichloromethane as eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH:17]4[CH2:19][CH2:18]4)=[CH:4][CH:3]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1)=[O:24])[CH3:21]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCC1CC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-cyclopropylmethyl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH2:29]([O:31][C:32](=[O:45])[CH:33](P(OCC)(OCC)=O)[CH:34]([CH3:36])[CH3:35])[CH3:30].[Li]CCCC>C1COCC1>[CH2:29]([O:31][C:32](=[O:45])[C:33](=[CH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=3)[CH:11]=[C:2]([CH3:1])[C:3]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][CH:21]=1)[CH:34]([CH3:35])[CH3:36])[CH3:30]
Reactant: CCOC(=O)C(C(C)C)P(=O)(OCC)OCC
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1)C(C)C

Procedure:
Using the procedure described in Example 31 (Step 3), reaction of 4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-benzaldehyde (8) (0.507 g, 1.38 mmol), 2-(diethoxy-phosphoryl)-3-methyl-butyric acid ethyl ester (1.1 g, 4.13 mmol) and 1.6 M nBuLi (2.8 mL, 4.41 mmol) in dry THF (14 mL) afforded 2 isomeric products (222) as oils. Yield: (222-1) Isomer (1) 0.177 (27%); (222-2) Isomer (2) 0.195 g (30%). Isomer (1): 1H NMR (400 MHz, d-CDCl3): δ 1.20 (d, J=6.9 Hz, 6H), 1.32 (t, J=7.1 Hz, 3H), 2.24 (s, 3H), 3.06-3.10 (m, 1H), 3.94 (s, 3H), 4.20-4.25 (m, 2H), 6.58 (d, J=8.8 Hz, 2H), 7.03-7.07 (m, 3H), 7.12-7.14 (m, 3H), 7.22-7.26 (m, 3H), 7.39 (s, 1H), 7.56 (s, 1H), 7.78 (d, J=9.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([Cl:15])[CH:3]=1.Cl.C(O)C.O=[C:21]([C:27](OCC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CO.[C].[Pd]>[NH2:14][S:11]([C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[Cl:15])[N:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27](=[O:28])[NH:8]2)(=[O:13])=[O:12]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a solution of 4-amino-2-chloro-5-nitrobenzenesulfonamide (2.00 g, 7.95 mmol) in methanol (40 ml) were added 10% palladium-carbon (400 mg) and successively 10% hydrochloric acid (6 ml) at room temperature, and catalytic hydrogenation was conducted for 2 hours at ambient temperature under ambient pressure. Catalyst was filtered off using celite and the filtrate was distilled off under reduced pressure. After dissolved this into ethanol (16 ml), diethyl ketomalonate (1.21 ml, 7.95 mmol) was added, which was stirred for 5 hours at room temperature. The precipitate was collected by filtration, washed with ethanol and then purified by means of silica gel column chromatography [hexane-ethyl acetate=1:2] to obtain 288 mg of the title compound. Yield 11%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>C(O)CCC>[OH:20][CH2:19][CH2:21][NH:22][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Reactant: NCCO
Solvent: CCCCO
Product: CCCOc1ccccc1-c1nc(NCCO)cc(=O)[nH]1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.43 g) and ethanolamine (0.3 g) in n-butanol (8 ml) was heated under reflux for 4 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was washed with diethyl ether and then eluted from silica with chloroform:methanol (gradient elution). The combined fractions containing product were evaporated under reduced pressure to yield a crude product which was recrystallized from isopropanol:diethyl ether to yield the title compound, 0.28 g, m.p. 164.5-165.5° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[C:13](=[N:26]O)[C:12]1=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1>[NH2:26][CH:13]1[C:14]2[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[C:12]1=[O:28]
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(=O)c(=NO)c2ccccc2c2cccnc21
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N)c2ccccc2-c2cccnc21
Temperature: 62.5 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
Combine 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7-hydroxyimino-pyrido[2,3-d][3]benzazepin-6-one (206.0 g, 0.52 mol) and tetrahydrofuran (2.3 L) into an autoclave under an atmosphere of nitrogen. Add Raney nickel (232.0 g, 1.13 wt/wt equivalents) to the reaction mixture and introduce hydrogen atmosphere (87 psi). Stir the reaction mixture at 60-65° C. for 24 hours. Filter the mixture over diatomaceous earth and wash the filter aid with tetrahydrofuran (500 mL). Concentrate the filtrate to obtain the title compound (196.0 g, 93.2%) as a brown oil. MS (m/z): 384 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10](Br)[CH:11]=[CH:12][C:13]=2[O:17][CH3:18])[NH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:17][CH3:18])[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Br)ccc(OC)c2c1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cccc(OC)c2c1=O
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol) and 10% Pd/C (100 mg) in glacial acetic acid (50 mL) was stirred under H2 (2.5 atm) overnight. The catalyst was removed via filtration, and the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in CH2Cl2 (100 mL) and washed with aqueous sodium bicarbonate solution and water. The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography to afford 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester as a yellow solid (1 g, 57%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1C=CC=CC=1>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1
Yield: 88.6 %

Procedure:
The preparation of Example 1 was repeated with the changes that tert-butyl amine (4.02 g, 0.055 mole) and 4-bromobenzoyl chloride (6.04 g, 0.0275 mole) were the starting reactants and benzene was the reaction medium. This reaction produced 6.24 g crystals (89% yield), mp 130°-133° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.562 ppm (s, 4H; aryl H); 5.910 ppm (bs, 1H; N-H); 1.464 ppm (s, 9H; tert-butyl H).