Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.CC(C)([O-])C.[Na+].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.[CH3:69][O:70][CH2:71][CH2:72][NH:73][CH3:74]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:69][O:70][CH2:71][CH2:72][N:73]([CH3:74])[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([NH:8][CH3:9])=[CH:6][N:7]=1
Reactant: CNCCOC
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CNc1cnc(N(C)CCOC)cc1-c1ccccc1C
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
6-Chloro-N-methyl-4-o-tolylpyridin-3-amine (60 mg, 0.26 mmol, prepared as described in WO2005/002577), sodium tert-butoxide (74 mg, 0.77 mmol), palladium acetate (5.8 mg, 0.026 mmol, CAS RN 3375-31-3) and BINAP (48 mg, 0.077 mmol, CAS RN 76189-55-4) were dissolved in toluene (3 mL) and stirred under an argon atmosphere for 10 minutes. N-(2-Methoxyethyl)methylamine (46 mg, 0.52 mmol, CAS RN 38256-93-8) was added and the reaction mixture was sealed and heated to 150° C. under microwave irradiation for 30 min. The reaction mixture was columned directed on silica gel (EtOAc) to yield the product as a light brown oil (36 mg, 49%). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[CH:14]1[CH2:19]COC[CH2:15]1.CC1(C)C(C)(C)OB(C2C[CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]C=2)O1>>[CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:5]([CH:14]2[CH2:19][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:15]2)=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(OC)c1nc2c(cc1C1CCOCC1)CCCN2
Product: COC(OC)c1nc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)CCCN2

Procedure:
The title compound was synthesized in an analogous manner to intermediate 312 by replacing 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate. The title compound was obtained as a white foam. (UPLC-MS 3) tR 0.80 min; ESI-MS 392.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[N:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:7]1[C:8]2[CH2:9][CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][C:14]=2[C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[N:30]=[N:31][C:26]([C:25]([F:39])([F:24])[F:40])=[CH:27][CH:28]=4)=[CH:33][C:34]3=[O:38])=[N:23][C:6]1=2
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.13 g, 0.35 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (85 mg, 0.35 mmol), and Cs2CO3 (0.13 g, 0.39 mmol) were suspended in DMSO (2.0 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (15 mg, 0.11 mmol) and copper iodide (86 mg, 0.45 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2(30 mL) and washed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (47 mg, 24%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=9.0 Hz, 1H), 8.47 (d, J=8.5 Hz, 1H), 8.12 (d, J=7.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.40-7.39 (m, 2H), 7.22 (dd, J=7.0, 2.0 Hz, 1H), 3.73 (s, 3H), 3.71-3.69 (m, 2H), 3.61-3.60 (m, 2H), 3.09-3.08 (m, 2H), 2.99-2.89 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C@@H:13]1[C@@H:17]([CH2:18][CH2:19][C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:15][C@@H:14]1[CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:54]1([CH3:64])[CH:59]=[CH:58][C:57]([S:60](Cl)(=[O:62])=[O:61])=[CH:56][CH:55]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:64][C:54]1[CH:59]=[CH:58][C:57]([S:60]([O:43][CH2:42][C@H:14]2[CH2:15][C@@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:17]([CH2:18][CH2:19][C@@H:20]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:13]2[CH2:12][C:11]2[CH:44]=[CH:45][CH:46]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)(=[O:62])=[O:61])=[CH:56][CH:55]=1
Reactant: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethylsilyloxy)-3-((S)-3-(tert-butyldimethylsilyloxy)octyl)cyclopentyl)methanol (0.3 g, 0.45 mmol) in dry CH2Cl2 (3 ml) was cooled to 0° C. under nitrogen and treated with triethylamine (0.12 ml, 0.9 mmol) and trace amount 4-(dimethylamino)pyridine (DMAP), then p-toluenesulfonyl chloride (0.13 g, 0.67 mmol) was added and the reaction was stirred at room temperature. After the reaction was completed, 20 ml saturated NaHCO3 was added and extracted with CH2Cl2, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent. to give the titled compound 0.2 g, yield 54%.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH:33]=O)[CH:28]=1>>[Br:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH2:6][CH2:5][CH2:4][O:3][CH3:2])[CH:28]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COCCCCc1cc(Br)ccn1

Procedure:
Analogously to residue 1a, 2,4 mmol of (3-methoxypropyl)triphenylphosphonium bromide [111088-69-8] and 1.6 mmol of 4-bromopyridine-2-carbaldehyde [131747-63-2] are reacted. The title compound (E,Z mixture) is identified on the basis of the Rf value.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][CH2:12][CH3:13])=[O:5])C.[ClH:14]>O>[ClH:14].[CH2:11]([C:10]1[NH:9][CH:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3])[CH2:12][CH3:13]
Reactant: CCCc1[nH]cnc1C(=O)OCC
Agent: Cl
Solvent: O
Product: CCCc1[nH]cnc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
5-Propyl-1H-imidazole-4-carboxylic acid ethyl ester 2 (2.00 g; 11.0 mmol) and concentrated aqueous HCl (40 mL) were combined and heated to reflux with stirring for 24 h. After cooling to rt, the light tan solution was diluted with water (100 mL) and extracted with EtOAc. The aqueous layer was then evaporated under reduced pressure. The residue was dissolved in 2-propanol (20 mL) and cooled to −78 C. Upon addition of Et2O, a white precipitate formed. This material was collected by filtration and dried under vacuum to afford 2.10 g (100%) of 3. 1H NMR (DMSO-d6): δ 0.87 (t, 3H), 1.69 (m, 2H), 2.92 (t, 2H), 9.17 (s, 1H); 13C NMR (DMSO-d6): δ 13.9, 22.4, 26.4, 120.9, 135.7, 140.0, 160.7; Anal. calcd for C7H11ClN2O20.66(C3H9O)0.33(H2O): C, 45.67; H, 7.24; N, 11.84; Cl, 14.98; found: C, 45.27; H, 7.17; N, 11.86; Cl, 14.68.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:24](=[O:26])(=[O:25])[N:23]2[CH3:22])=[C:15]([CH3:21])[CH:16]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1C(=O)c1ccc2cccnc2c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1C1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 15.8 %

Procedure:
In a similar fashion using route 27 general procedure 71, (8-amino-quinolin-7-yl)-(4-fluoro-2-methyl-phenyl)-methanone (Intermediate 380) (200 mg, 0.71 mmol), N-methylsulfamyl chloride (Intermediate 213) (700 mg, 5.4 mmol), NaBH4 (81 mg, 2.14 mmol) and pyridine (6 ml) gave the title compound (40 mg, 16%) after purification by preparative HPLC (neutral conditions).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[CH:23]1([NH:29][C:5]2[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.5 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 60 mg of cyclohexylamine were dissolved in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 15 minutes. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed twice with 50 ml of 0.1 N aqueous sodium hydroxide solution, twice with 50 ml of 1 N aqueous hydrochloric acid and with 50 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (41 mg) with a molecular weight of 288.4 g/mol (C13H24N2O3S); MS (ESI): m/e=289 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)O)cc2OCCCC)c1
Temperature: 50 °C
Yield: 62.3 %

Procedure:
40 mg (1 mmol) of sodium hydroxide are added to a solution of 526 mg (1.1 mmol) of ethyl (E)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methylacrylate in 1 mL of ethanol and 10 mL of tetrahydrofuran. The reaction mixture is heated at 50° C. for 24 hours. The reaction medium is evaporated to dryness, taken up in water and acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture and then precipitated from heptane. 310 mg (91%) of (E)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methylacrylic acid are obtained in the form of a white solid with a melting point of 87-89° C.
Reaction SMILES: [Mg].CI.Br[C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]=1[O:16][CH3:17].[CH3:18][C:19]1([CH3:28])[O:23][C@@:22]([CH3:27])([CH2:24][CH:25]=[O:26])[CH2:21][O:20]1.[Cl-].[NH4+].S(=O)(=O)(O)O>O1CCCC1>[CH3:17][O:16][C:6]1[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:5]=1[CH:25]([OH:26])[CH2:24][C@@:22]1([CH3:27])[CH2:21][O:20][C:19]([CH3:18])([CH3:28])[O:23]1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: CC1(C)OC[C@](C)(CC=O)O1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(C(O)C[C@@]2(C)COC(C)(C)O2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.8 g of magnesium shavings activated with methyl iodide was added dropwise a solution of 7.77 g of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene in 20 ml of absolute tetrahydrofuran at a rate such that the solvent was brought just to boiling. Subsequently, the reaction mixture was boiled under reflux for an additional hour. To this Grignard solution, cooled down to 0°, were added dropwise 5.0 g of (S)-2,2,4-trimethyl-1,3-dioxolan-4-acetaldehyde. Subsequently, the reaction mixture was stirred at room temperature for a further 4 hours and under reflux for 15 minutes. For the working-up, the reaction mixture was cooled down to 0°, it was treated with 10 ml of saturated ammonium chloride solution followed by 10 ml of 2-N sulfuric acid and extracted with a total of 0.5 l of ether. The organic phase was washed neutral with water and dried over magnesium sulfate. After removal of the solvent on a rotary evaporator and drying of the residue in a high vacuum, there were obtained 10.5 g of a highly viscous oil, which, for purification, was chromatographed on 450 g of Kieselgel with ether/hexane/acetic ester (4:4:1 parts by volume). The yield of α-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2,4-(S)-trimethyl-1,3-dioxolan-4-ethanol amounted to 8.83 g; [α]D20 =-5.5° (c=1.20; CHCl3).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14]>CO>[C:1]([NH:9][N:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: C/C=C/C=O
Reactant: NNC(=O)c1cccnc1
Solvent: CO
Product: C/C=C/C=NNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 50 ml of methanol was suspended 22 g of nicotinic acid hydrazide. To the suspension was added dropwise 13.2 ml of crotonaldehyde, followed by stirring for 30 minutes at room temperature. Methanol was distilled away under reduced pressure, and the residue washed with ether, filtered off, and dried. Thus there was obtained 27.5 g of crotonaldehyde nicotinoyl hydrazone (mp. 144°-145° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([CH3:18])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)O.[OH-].[Na+]>ClCCl.S(=O)(=O)(O)O>[Cl:23][C:21]1[CH:20]=[C:19]2[C:3](=[C:2]([Cl:1])[CH:22]=1)[CH2:4][N:5]([CH3:18])[CH2:6][CH:7]2[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanol (14 g, 39.55 mmol, 1.00 equiv) in dichloromethane (140 mL), sulfuric acid (140 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 100 mL of ice. The pH value of the solution was adjusted to 8-9 with sat. sodium hydroxide (100 mL). The resulting solution was extracted with 2×500 mL of ethyl acetate and the organic layers combined and dried over sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10˜1:5). This resulted in 7 g (51%) of 6,8-dichloro-2-methyl-4-(3-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline as a yellow solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:33]N)[CH:29]=[CH:30][C:31]=1[F:32]>>[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccc(F)c(F)c1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(F)c(F)c3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3,4-difluoro-phenylhydrazine according to the method described for example 91. MS: M=429.2 (M+H)+
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.Cl.CCOCC>C1COCC1.CCCCCC>[CH3:1][NH:2][C:3](=[O:11])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:15][CH2:14][N:13]([CH3:17])[CH3:12]
Reactant: CN(C)CCCl
Reactant: CNC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(=O)C(CCN(C)C)c1ccccc1
Yield: 83.5 %

Procedure:
To 7.46 g (0.05 mol) of N-methyl phenylacetamide (prepared by reaction of phenylacetyl chloride with monomethylamine in CH2Cl2 solvent) dissolved in 70 ml of THF and cooled in an ice-bath to 0°, was added dropwise with stirring under N2, 40 ml (0.10 mol) of a 2.5M solution of N-BuLi in n-hexane. After stirring at 0° for 30 min, the solution was treated by the rapid addition of 5.4 g (0.05 mol) of 2-(dimethylamino)ethyl chloride in 30 ml of THF and then stirred at 0° for 30 min. The reaction mixture was then poured into 250 ml of 1N HCl, ether was added and the aqueous layer was separated, basified with 2.5N NaOH and extracted with Et2O. The ether extract was dried (Na2SO4), concentrated, and kugelrohr distilled to afford 9.2 g (83.5%) of N-methyl-4-dimethylamino-2-phenylbutanamide as a viscous. colorless oil; bp 130°-135°/0.1 mm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH:19]=1)=[O:4].[OH-].[Na+]>C(O)C>[CH:7]1[C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH:19]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2

Procedure:
5.6 G. methyl-10,11-dihydrodibenzo[b,f]-thiepin-3-carboxylate is refluxed in a mixture of 50 cc. 20% aqueous sodium hydroxide and 50 cc. ethanol until a clear solution results (15 to 20 minutes). Most of the ethanol is evaporated away and aqueous residue is diluted with water and acidified with hydrochloric acid. The white solid is collected, recrystallized from acetic acid to yield 4.125 g. (77.7%) of the desired white crystalline material, m.p. 196°-198° C. Calculated: C: 70.29; H: 4.72; S: 12.51. Found: C: 69.92; H: 4.71; S: 12.15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In N,N-dimethylformamide (40 mL) was dissolved 4-bromo-2-methyl-phenol (1.87 g), potassium carbonate (4.15 g) and benzyl bromide (1.3 mL) were added to the solution, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate, and the liquids were separated. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2 to 95:5) to obtain 1-benzyloxy-4-bromo-2-methylbenzene (2.73 g).
Reaction SMILES: O.[CH2:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[C:7](OCC)(=[O:10])[C:8]#[CH:9].[Na+].[Cl-]>C(O)(=O)C>[CH2:2]([NH:6][C:7](=[O:10])[C:8]#[CH:9])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN
Reactant: C#CC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CC(=O)NCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 30 mL of water and 7.68 g (105 mmol) n-Butylamine is added dropwise 9.8 g (100 mmol) ethyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 2 h at 0° C., then acetic acid (2 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (12.0 g, yield 95%, purity 69% by GC).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23](=[O:38])[NH:24][CH2:25][C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]4[CH:37]=[CH:36][N:35]=[CH:34]4)[N:27]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C)C=O>[N:33]1([C:28]2[N:27]=[C:26]([CH2:25][NH:24][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][NH:18]3)=[O:38])[CH:31]=[C:30]([CH3:32])[N:29]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: Cc1cc(CNC(=O)C2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)nc(-n2ccnc2)n1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)C2CCCN2)nc(-n2ccnc2)n1
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a solution of 2-[(2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (435 mg, 0.855 mmol) in dimethylformamide (3.2 mL) was added piperidine (800 μL, 8.09 mmol) at r.t. The solution was stirred for 20 min then concentrated under vacuum to afford 244 mg of pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide as a brown oil. [M+H]+ 287.28.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCc1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
(4,6-dichloropyrimidin-5-yl)acetaldehyde (2.96 g, 15.5 mmol) was dissolved in methanol (60 mL) and cooled at 0° C. Sodium tetrahydroborate (0.879 g, 23.2 mmol) was added and the mixture was stirred for 1 hour. TLC indicated complete conversion. The reaction was quenched with water (20 mL), methanol was removed in vacuo and the residue was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The residue was purified using chromatography on silica gel using gradient 0 to 100% ethyl acetate in methylene chloride to afford the title compound (1.90 g, 63%). LC/MS: Rt=0.93 min, ES+ 194 (AA standard).