Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15](Cl)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH:33](O)[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C1C=CC=CC=1.C(OCC)(=[O:44])C.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([O:44][CH2:34][CH2:33][N:30]3[CH2:31][CH2:32][N:27]([C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=4)[CH2:28][CH2:29]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(O)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc(C(=O)c2ccc(Cl)cc2)c1)OCCN1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Using the procedure of Example 2, 3-(4-chlorobenzoyl)-benzeneacetic acid chloride was reacted with 4-(4chlorophenyl)-1-piperazinyl-ethanol to obtain 2-[4-(4-chlorophenyl)-1-piperazinyl]-ethyl 3-(4-chlorobenzoyl)-benzeneacetate with an Rf=0.68 (9-1-0.05 benzene-ethyl acetate-triethylamine eluant). Treatment with hydrochloric acid resulted in the formation of the hydrochloride salt melting at 142° C.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.C[NH:13][CH2:14][CH2:15][NH:16][CH3:17].[C:18]1(C)C=CC=CC=1>>[CH3:18][N:16]([CH3:17])[CH2:15][CH2:14][NH:13][C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1
Reactant: CSc1nncc2cncn12
Reactant: CNCCNC
Reactant: Cc1ccccc1
Product: CN(C)CCNc1nncc2cncn12

Procedure:
A 5.0 gm. portion of 4-(methylthio)-imidazo[1,5-d]-as-triazine in a mixture of 30 ml. of unsymmetrical dimethylethylenediamine and 20 ml. of toluene is reacted as described in Example 40 giving the desired product as light yellow crystals, m.p. 172°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[N+]1([O-])C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][N:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3nc[nH]c3c2)c(SC)s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3ncn(-c4ccccc4)c3c2)c(SC)s1
Yield: 51.3 %

Procedure:
4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester was prepared according to literature (Lam, P. Y. S. et al., Tetrahedron Letters, 42:3415 (2001)) using 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (20 mg, 44.7 μmol, Example 38: step e), phenylboronic acid (11.4 mg, 93.5 μmol), Cu(OAc)2 (8.5 mg, 46.8 μmol), pyridine N-oxide (4.7 mg, 49.2 μmol), triethylamine (13 μL, 93.3 μmol), and CH2Cl2 (1.5 mL) in a loosely-capped, 1-dram vial. The reaction mixture was diluted in CH2Cl2 and washed with water and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC afforded the title compound as a brown oil (12 mg, 51%). ESI-MS (m/z): Calcd. for C20H15N2O4S3: 522.9 (M+1); found: 525.0.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl-:17].[P+]=O>ClCCCl>[Cl:17][C:7]1[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccc[n+]([O-])c1-c1ccccc1
Agent: O=[P+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(Cl)nc1-c1ccccc1
Temperature: 25 °C

Procedure:
In a 100 ml single-necked round-bottomed flask equipped with a condensor, 5.00 g of 3-nitro-2-phenyl-pyridine-1-oxide is dissolved in 25.0 ml dry 1,2-dichloroethane. Phosphorous oxide chloride (3.18 ml) is added carefully (yellow-orange solution). This mixture is then stirred under heating to reflux for 17 h. After cooling the mixture to ambient temperature. Ice/water is added then. The extraction is carried out with dichloromethane (2×50 ml). After washing with brine, the organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography over a silica gel cartridge (25 g, 150 ml) of a solid deposition with hexane/ethyl acetate 4:1 (v:v) gives 2.61 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]2[O:16][CH2:17][O:18][C:9]=2[CH:8]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([NH2:13])=[CH:11][C:10]2[O:16][CH2:17][O:18][C:9]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1cc2c(cc1N)OCO2
Yield: 98.8 %

Procedure:
The solution of 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (0.8 g, 3.13 mmol) in ethyl acetate (25 ml) was subjected to catalytic hydrogenation using 10% palladium on carbon (100 mg) at 50 psi for 30 min. The catalyst was filtered and the solvent was removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy)-6-aminophenyl]ethane as a solid (0.69 g, 98% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[NH2:38][C@H:39]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)=[CH:47][CH:46]=1)[CH2:40][C:41]([OH:43])=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:38][C@H:39]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)=[CH:47][CH:46]=1)[CH2:40][C:41]([OH:43])=[O:42])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A solution of succinic acid mono-benzyl ester (71.1 mg, 0.342 mmol), EDCl (65.5 mg, 0.342 mmol) and HOAt (46.5 mg, 0.342 mmol) in DMF (1 ml), which is allowed to stir at room temperature for 1 hour, is added to a solution of (R)-3-amino-4-(3′-chlorobiphenyl-4-yl)butanoic acid (66 mg, 0.228 mmol) and DIPEA (0.080 ml, 0.456 mmol) in a mixed solvent DMF (2 ml) and water (2 ml). The reaction mixture is allowed to stir for 3 hours, and then diluted with H2O. The products are extracted twice with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4-(benzyloxy)-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (42.4 mg) as a white solid; HPLC retention time=1.22 minutes (condition B); MS (m+1)=480.35; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44-2.75 (m, 6H) 2.86-2.99 (m, 2H) 4.48-4.56 (m, 1H) 5.11 (s, 2H) 6.29 (br d, J=8.6 Hz, 1H) 6.97-7.07 (m, 10H) 7.25-7.36 (m, 2H) 7.42-7.50 (m, 2H) 7.54 (br t, J=1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][F:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][F:26])[C:17]([OH:19])=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCF)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CCF)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
359 mg (853 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoate (racemate) in 8.5 ml of dichloromethane and 2.5 ml (32 mmol) of TFA were reacted according to General Method 6A. Yield: 306 mg (96% of theory)
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([C:37]([C:39]2[N:40]=[CH:41][N:42]3[CH:46]=[C:45]([Sn](CCCC)(CCCC)CCCC)[S:44][C:43]=23)=[O:38])[CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:45]3[S:44][C:43]4=[C:39]([C:37]([C:29]5[CH:28]=[N:27][C:36]6[C:31]([CH:30]=5)=[CH:32][CH:33]=[CH:34][CH:35]=6)=[O:38])[N:40]=[CH:41][N:42]4[CH:46]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cnc4ccccc4c3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cnc6ccccc6c5)c4s3)[C@H](C)[C@H]12
Yield: 42.4 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinolin-3-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (86 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 180 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 185 mg of 7-(quinolin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[N:24]=[CH:25][C:26]([CH2:29][N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[CH:27][N:28]=4)[CH:18]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=Cc1cnc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)nc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cnc(-c3cccc(Cn4nc(-c5cc(F)cc(F)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
7.2 A suspension of 472 mg (1.17 mmol) of 2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carbaldehyde in 5 ml of dichloromethane is given successively with 166 μl of 1-methylpiperazine, 495 mg (2.34 mmol) of sodium triacetoxyborohydride and 67 μl of acetic acid, and the reaction mixture is stirred at room temperature for 42 hours. The reaction mixture is partitioned between dichloromethane and 1 N NaOH. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent: 6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-ylmethyl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one (“A14”) as colourless crystals; ESI 489;
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[F:10])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[NH2:17][OH:18].Cl>CCO.O>[NH2:7][C:6]1[CH:8]=[CH:9][C:3]([C:1](=[NH:2])[NH:17][OH:18])=[C:4]([F:10])[CH:5]=1
Reactant: N#Cc1ccc(N)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(N)cc1F
Temperature: 60 °C
Yield: 60.3 %

Procedure:
4-cyano-3-fluoroaniline (10 g, 0.0735 mol) was dissolved in EtOH (36.7 ml) and water (7.3 ml), Na2CO3 (5.06 g, 0.65 eq) was added. The mixture was heated at 60° C. and a solution of NH2OH.HCl (5.615 g, 1.1 eq) in water (7.3 ml) was added slowly, the mixture was heated at 60° C. overnight. The mixture was cooled to 0° C., and the solid collected by filtration. Washed with water (7 ml), EtOH (7 ml), Et2O (20 ml) and dried to give 7.5 g of compound 139-1.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1([CH3:9])[CH2:8][O:7][CH2:6]1.[H][H].Cl[CH2:13][C:14]1([CH2:18]Cl)[CH2:17][O:16][CH2:15]1>CN(C=O)C>[CH3:9][C:5]1([CH2:4][O:3][CH2:13][C:14]2([CH2:18][O:3][CH2:4][C:5]3([CH3:9])[CH2:8][O:7][CH2:6]3)[CH2:17][O:16][CH2:15]2)[CH2:8][O:7][CH2:6]1
Reactant: ClCC1(CCl)COC1
Reactant: CC1(CO)COC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCC2(COCC3(C)COC3)COC2)COC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Sodium hydride (50% dispersion in mineral oil, 32.68 g, 0.681 mol) was washed twice with hexanes and was suspended in 600 mL of DMF. Then, 3-hydroxymethyl-3-methyloxetane (69.46 g, 0.681 mol) was added dropwise over 45 min while hydrogen gas was evolved and a beige solid precipitated. The mixture was stirred for 30 min and a solution of 3,3-bis-(chloromethyl)oxetane (40.61 g, 0.262 mol) in 50 mL of DMF was added. The mixture was heated to 100° C. for 64 h when 1H NMR analysis of an aliquot showed that the starting halide had been consumed. The mixture was poured into 600 mL of water and extracted with two portions of 200 mL of methylene chloride. The combined organic extracts were washed with 3 portions of 150 mL of water, dried over magnesium sulfate, and evaporated to give 74.8 g, representing a 91% yield of 3,3-bis-[(3-methyl-3-oxetanyl)methyloxymethyl]oxetane as an oil containing DMF (8.8%). The oil was purified by bulb-to-bulb distillation at 130° C. and 0.1-mm pressure to give 49.83 g, representing a 77% yield, of analytically pure ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:16])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH:17]([NH:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[S:22])([CH3:19])[CH3:18].CC(C)=O>C(O)(=O)C>[ClH:16].[CH2:1]([O:3][C:4]([C:6]1[C:7]([S:22][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:20][CH:17]([CH3:19])[CH3:18])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Reactant: CC(C)NC(=S)NC(C)C
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCOC(=O)c1nc2ccccc2nc1SC(=NC(C)C)NC(C)C
Product: Cl

Procedure:
2-Chloro-3-quinoxalinecarboxylic acid ethyl ester (4.73 g., 0.02 mole) and 3.206 g. (0.02 mole) of 1,3-diisopropylthiourea were dissolved in 90 ml. of acetone and 10 ml. of acetic acid. The solution was heated on the steambath for 23/4 hours and filtered hot. The solvent in the filtrate was evaporated and the residue was triturated with ether until it solidified. Filtration gave 2.33 g. of crude product. Recrystallized from acetone-ether it afforded 1.28 g. (16.1%) of a yellow solid, m.p. 148°-149° C. (dec).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:21])[N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:21][CH:10]1[CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12][N:11]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2CCNC2C1C

Procedure:
16 g (55 mmol) of ethyl 2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane -7-carboxylate in 300 ml of ethanol are hydrogenated at 100° C. and 100 bar on 3 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:30]([CH3:32])[CH3:31]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH:30]([CH3:32])[CH3:31])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(O)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Reactant: CC(C)I
Product: CCc1cc(OC(C)C)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Yield: 100 %

Procedure:
1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl -6-isopropoxy benzene was prepared in 100% yield as a white solid from 1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and 2-iodo-propane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([CH3:20])=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Reaction time: 0.17 h

Procedure:
To a solution of 5.465 g (20 mmol) 2-(2-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 60 ml dry THF were added at <−60° C. 11.0 ml (22 mmol) lithium diisopropylamide solution 2M in THF/heptanes/ethylbenzene and the mixture stirred for 1.5 h at <−60° C. To the resulting dark brown solution were added 2.5 ml (40 mmol) iodomethane drop wise over 10 min (exothermal, Ti <−48° C.). The resulting light brown solution was stirred at <−50° C. for 2.5 h then quenched with sat. aq. NH4Cl solution and extracted three times with tert-butyl methyl ether. The combined organic phases were washed 3× with brine, dried over Na2SO4, filtered and evaporated: 7.002 g yellow solid: which was purified by flash-chromatography on silica gel with heptane and 5 to 10% AcOEt over 25 min and heptane/AcOEt 90:10 for 20 min. 2-(2-Methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was obtained as light yellow oil: MS (ISP): 288.12 ((M+H)+).
Reaction SMILES: [OH-].[Li+].O.[Cl:4][C:5]1[C:9]([CH2:10][N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])=[CH:8][S:7][C:6]=1[C:23]([O:25]C)=[O:24]>O1CCOCC1>[Cl:4][C:5]1[C:9]([CH2:10][N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])=[CH:8][S:7][C:6]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1scc(CN(C)S(=O)(=O)c2ccc(Cl)cc2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(Cc1csc(C(=O)O)c1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 84.2 %

Procedure:
Lithium hydroxide (210 mg, 5.0 mmol) and water (10 ml) were added to a solution of methyl 3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carboxylate (990 mg, 2.5 mmol) in dioxan (20 ml) and the mixture stirred for 18 h. The mixture was evaporated and 0.3N potassium hydrogen sulphate was added. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, dried and reduced to afford 3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carboxylic acid (800 mg, 84%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]=1[C:16]([F:19])([F:18])[F:17].Cl>>[F:17][C:16]([F:19])([F:18])[C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[OH:1]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 90 %

Procedure:
To a 1000 cm3 flask equipped with a stirrer, dropping funnel, reflux and thermometer 300 g /0.75 mole/ of a 10% by weight NaOH solution are added 81.3 g /0.3 mole/ of 2-chloro-3,5-dinitro-benzotrifluoride of a purity of 95% are added under stirring. The temperature is raised to 60° C. and the reaction mixture is stirred at 60°-65° C. for 4 hours, while the aqueous suspension forms an emulsion. The reaction mixture is then cooled to room temperature /20°-25° C./ under stirring and within 1 hour a 37% hydrochloric acid solution corresponding to 0.82 mole HCl is added in equal portions under vigorous stirring. The precipitated product is filtered, washed with water and dried to constant weight at room temperature. 2-Trifluoromethyl-4,6-dinitro-phenol is obtained /68.1 g., purity: 94%/ Idenfication was carried out by a mass spectrometer connected to a gas chromatograph.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:22][C:9]2=3)=[N:4][N:3]=1.[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:44]([S:1][C:2]1[S:6][C:5]([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:22][C:9]2=3)=[N:4][N:3]=1)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc2c(c1)C(Sc1nnc(S)s1)c1ccccc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCSc1nnc(SC2c3ccccc3COc3ccc(C(=O)OC)cc32)s1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
After 50 ml of an N,N-dimethylformamide solution containing a mixture of 2.0 g of Compound 153a obtained in Example 119, 2 ml of octadecyl bromide and 2.0 g of potassium carbonate was stirred at 80° C. at 1.5 hours, the solvent was distilled off under reduced pressure. The aqueous phase was extracted with 200 ml of methylene chloride. The extract was washed with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=15:1) to give 0.8 g of the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1.[OH-:15].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([OH:15])[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1
Reactant: CCc1nc2cc(Cl)nc(SC)n2n1
Reactant: [OH-]
Agent: [K+]
Product: CCc1nc2cc(Cl)nc(O)n2n1

Procedure:
In analogy to Example 33A, 242 mg (99% of theory) of the product are obtained from 280 mg (1.22 mmol) of 7-chloro-2-ethyl-5-(methylsulphanyl) [1,2,4]triazolo[1,5-c]pyrimidine (Example 101A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[N:17]1([S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18]1
Reactant: C1CNC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1Cl
Yield: 47.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmol), azetidine hydrochloride (320 mg, 3.44 mmol) and triethylamine(1.44mL, 10.32 mmol) were reacted to form the desired product (510 mg, 48%). 1H NMR (MeOD-d4): δ 7.94 (d, 1H), 7.79 (d, 1H), 4.16 (t, 4H), 2.29 (m, 2H).