Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:31][CH2:32]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(S(C)=O)cc1C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylsulfinylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography on silica gel eluting with 10% methanol/dichloromethane, the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:26](=[O:30])/[CH:27]=[CH:28]/[CH3:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH:28]([CH3:29])[CH2:27][CH:26]=[O:30])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: C/C=C/C=O
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(CC=O)P(=O)(O)CCCCc1ccccc1

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.0025 mole) in chloroform (15 ml) was added triethylamine (0.77 ml, 0.005 mole), trimethyl silylchloride (0.70 ml, 0.005 mole) and crotonaldehyde (0.23 ml, 0.0025 mole). The reaction mixture was stirred at reflux temperature for 18 hours. The chloroform was removed in vacuo. The residue was diluted with ether and extracted with 5% NaHCO3 solution. The aqueous layer was acidified with concentrated HCl and extracted twice with ether and once with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a solid which was dissolved in CH3OH; ether and hexane were added until turbidity. The mixture was kept in a freezer overnight, yield 0.099, m.p. 138° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.O.O.O.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:14]1[C:13]([CH3:12])=[N:17][CH:16]=[N:15]1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Yield: 22.3 %

Procedure:
3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), 3-methyl-1H-1,2,4-triazole (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in dimethyl sulfoxide (1.5 mL) were stirred for 6 hours at 70° C. The mixture was concentrated in vacuo; the residue was diluted in water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried with magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (160 mg, 22%) as white crystals MS ISP (m/e): 223.2[(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.22 (m, 2H), 8.04 (s, 1H), 7.74 (dd, 1H), 2.48 (d, 3H). Mp 56-58° C.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[C:8](=O)[C:7]2=[O:17].Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22]>>[OH2:3].[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[C:7](=[O:17])[C:8](=[N:19][NH:20][C:21]([NH2:23])=[O:22])[C:9]2=[O:15]
Reactant: NNC(N)=O
Reactant: COc1cc2c(=O)c(=O)c(=O)c2cc1OC
Agent: Cl
Solvent: O
Product: COc1cc2c(=O)c(=NNC(N)=O)c(=O)c2cc1OC

Procedure:
5,6-dimethoxyindan-1,2,3-trione, monohydrate, semicarbazide hydrochloride
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:18])=[N:10][N:9]=1.[C:19]([O:23][C:24](=[O:33])[N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].O>CN1CCCC1>[Cl:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:29]2[CH2:28][CH2:27][CH:26]([N:25]([CH3:32])[C:24](=[O:33])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:31][CH2:30]2)=[N:9][N:10]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Cl)c3ccccc23)CC1
Yield: 36.6 %

Procedure:
Heat a mixture of potassium carbonate (21.23 g, 153.6 mmol), 1,4-dichlorophthalazine (26 g, 128 mmol) and methyl-piperidin-4-yl carbamic acid tert-butyl ester (30.01 g, 134.4 mmol) in N-methylpyrrolidine (200 mL) at 80° C. overnight. Pour the reaction mixture into water, extract with dichloromethane, dry over Na2SO4, and concentrate under reduced pressure. Add diethylether and filter off the resulting solid (4-chlorophethalazin-1-ol from starting material impurity). Concentrate the filtrate. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate=2:1) to provide the title compound as a white solid (17.66 g, 37%). ES/MS m/z (37Cl) 377.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[CH3:28][Si:29]([CH2:32][CH2:33][O:34][CH2:35]Cl)([CH3:31])[CH3:30].O>CN(C)C=O>[NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([O:18][CH2:35][O:34][CH2:33][CH2:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: C[Si](C)(C)CCOCCl
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnns3)CS[C@H]12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCOC(=O)C1=C(CSc2cnns2)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Reaction time: 0 h
Yield: 66.2 %

Procedure:
A mixture of 7-amino-3-[(1,2,3-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid (3.30 g, 10 mmol.) and triethylamine (1.40 ml, 10 mmol.) in 50 ml of dimethylformamide was stirred at room temperature for 1 0 hour. Trimethylsilylethoxymethyl chloride (1.80 ml, 10 mmol.) was added dropwise, the reaction mixture was stirred for 15 minutes at room temperature then poured into 100 ml of water and extracted with 80 ml of ethyl acetate. The ethyl acetate extract was washed with 75 ml aliquots of saturated sodium bicarbonate, water and brine then dried over magnesium sulfate. Evaporation of the solvent afforded 3.05 g of product as an amber oil: NMR (CDCl3) δ 0.03 [S, 9H, Si(CH3)3 ], 0.95 (t, 2H, J=7.5 Hz, --CH2Si), 2.00 (S, 2H, NH2), 3.50 (m, 4H, --OCH2Si and indocyclic --CH 2 --S--), 4.00 (S, 2H, oxocyclic --CH2S--), 4.60 (d, 1H, J=5.0 Hz, 6H of 7ACA), 4.80 (d, 1H, J=5.0 Hz, 7H of 7ACA), 5.30 (S, 2H, --OCH2O--), 8.40 (S, 1H, thiadiazole H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][N:11](C)C)[CH:5]=[CH:6][CH:7]=1.O.[NH2:22]N.C(OCC)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][NH:11][N:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1cccc(Br)c1)c1ccncc1
Reactant: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: Brc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
8 g (0.024 mol) of 1-(3-bromophenyl)-3-(dimethylamino)-2-pyridin-4-ylprop-2-en-1-one were dissolved in 20 ml of ethanol and 3 mL (0.06 mol) of hydrazine hydrate were added. The solution was refluxed under stirring for 4 hours. The title compound was collected by filtration. The filtrate was evaporated, the residue taken up with dichloromethane and washed with water. The organic layer, dried over Na2SO4, was evaporated to dryness and triturated with diethylether affording a second crop of the title compound (7.2 g overall; 100% yield).
Reaction SMILES: O1CCC[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[O:20][C:19]([CH3:27])([CH3:26])[CH2:18][C:17]2=O>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:2])[O:20][C:19]([CH3:27])([CH3:26])[CH:18]=[CH:17]2
Reactant: C1CCOC1
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOc1cc2c(cc1OC)C=CC(C)(C)O2
Yield: 88 %

Procedure:
In 80 ml of anhydrous tetrahydrofurane 5.0 g (20 millimoles) of 6-methoxy-7-methoxy-2,2-dimethyl-4-chromanone are dissolved whereupon 1.5 g of lithium aluminum hydride are added in small portions under stirring and the reaction mixture is heated to boiling for an hour. The reaction mixture is worked up according to Example 31. The product is purified by column chromatography. Thus 4.1 g of the desired compound are obtained in the form of a colorless oil, yield 88%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]4[C:16]([CH2:17][C:5]=3[C:4]=2[CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C@@H:6]3[C:11]4[C:16]([CH2:17][C@@H:5]3[C:4]=2[CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: Cc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Temperature: 0 °C

Procedure:
5,10-Dihydro-8-methylindeno[1,2-b]indole (10 g, 46 mmol) was stirred at room temperature in glacial acetic acid (150 cm3). Sodium cyanoborohydride (8.6 g, 3 equivalents) was added portionwise over a period of 30 minutes. The reaction was stirred for a further hour, and then poured into ice/water (200 cm3). After stirring for 30 minutes, the acidic solution was made basic by the addition of sodium hydroxide, and the colourless solid thus formed collected by filtration. This solid was washed copiously with water until the residue was free from cyanide ion, and then dried in a vacuum oven to yield the title compound as a colourless solid. Yield: 7.5 g (73%) M.p. 110° C. (from ethanol/water). 1H NMR (CDCl3) δ: 2.24 (3H, s,), 3.20 (1H, dd,), 3.50 (1H, dd,) 3.9 (1H, br,), 4.16 (1H, dd,), 5.23 (1H, d,), 6.52 (1H,d,), 6.80 (1H, d,), 6.99 (1H, s,), 7.1-7.4 (4H, m,).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:6].Cl>O1CCCC1.CO>[C:12]([N:10]1[CH:11]=[C:7]([C:5]([OH:6])=[O:4])[N:8]=[CH:9]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
Add 1N sodium hydroxide (22.8 mL, 22.8 mmol) to 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.8 g, 7.60 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) at room temperature. Stir the reaction mixture at room temperature for 5 hrs. Acidify the reaction mixture with 5N aqueous hydrochloride to pH about 6. Filter and dry the solid to give the title compound as a white solid (2 g, 5.64 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>O1CCOCC1>[CH:15]1([NH:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11]([NH2:14])(=[O:13])=[O:12])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NC1CC1
Reaction time: 24 h

Procedure:
2-Chloro-5-nitrobenzenesulphonamide (5 g) prepared in the Step above is introduced into a hermetically closed vessel containing a mixture of dioxane (70 mL) and cyclopropylamine (3.5 mL). The hermetically closed vessel is placed in an oven at 100° C. for 24 hours. After this time period, the solvent and the reagent are removed by concentrating under reduced pressure. The residue is taken up in methanol (20 mL) and the insoluble material, which contains the title product, is collected by filtration, washed with methanol and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-])=O)=[CH:5][C:6]([C:17]([F:20])([F:19])[F:18])=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C.O>[NH2:21][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[O:10])=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1N
Temperature: 65 °C
Yield: 79 %

Procedure:
To (5-methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone (349 mg, 1.04 mmol) in ethanol (20 mL) and water (2 mL) was added SnCl2.2H2O (941 mg, 4.16 mmol). The mixture was heated to 65° C. for 2 h and then 2 M aqueous sodium hydroxide solution (20 mL) and DCM (20 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (250 mg, 79%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=305 at 2.87 min. 1H NMR (400 MHz, CDCl3): δ 6.94 (s, 1H), 6.64 (s, 1H), 4.07 (s, 2H), 3.92-3.67 (m, 4H), 3.89 (s, 3H), 3.62-3.52 (m, 2H), 3.25-3.19 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.Cl>CCOCC>[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH:19]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:18][CH2:17]2
Reactant: Cc1ccc2c(c1)CCCC2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 6.1 h
Yield: 85.1 %

Procedure:
Ethyl trifluoroacetate (5.33 g, 37.5 mmol) was dissolved in ether (50 mL) and treated with a sodium methoxide solution (25% in methanol, 9.92 g, 45.9 mmol) followed by 6-methyltetralone (5.94 g, 37.1 mmol). The reaction was stirred at room temperature for 6.1 hours then treated with 3N HCl (20 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (8.09 g) that was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:29]=[C:24]1[NH:25][C:26](=[O:28])/[C:27](=[CH:1]\[C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:5][CH:4]=2)/[S:23]1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1ccc(OCCOc2ccc(C=O)cc2)cc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of 355 (1.59 g, 3.86 mmol) in toluene (10 mL) was added thiazolidine-2,4-dione (542 mg, 4.63 mmol), benzoic acid (61.3 mg, 0.50 mmol) and piperidine (57 uL, 0.58 mmol). The resultant mixture was refluxed with the Dean-Stark adapter for ½ h and cooled to the room temperature. A precipitate formed which was collected by filtration to afford the title compound (1.41 g, 92%). 1H NMR: (DMSO-d6) δ (ppm): 7.90 (d, J=8.8 Hz, 2H), 7.73 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.08 (d J=8.8 Hz, 2H), 4.42 (bs, 4H), 3.80 (s, 3H). LRMS (ESI): (calc.) 399.1; (found) 400.0 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[N:10][C:9]=1[OH:15].Cl[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.O>CS(C)=O.ClCCl>[Cl:7][C:8]1[C:9](=[O:15])[N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:11]=[CH:12][C:13]=1[Cl:14]
Reactant: ClCc1cccc2ccccc12
Reactant: Oc1nncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=c1c(Cl)c(Cl)cnn1Cc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 17 h
Yield: 67.6 %

Procedure:
9.0 g (65 mmol) of potassium carbonate were added to a solution of 10.0 g (60.61 mmol) of 4,5-dichloro-3-hydroxy-pyridazine in 50 ml dimethylsulphoxide, then 9.42 g (63 mmol) of 1-(chloromethyl)-naphthalene were added and the mixture was stirred for 17 hours at 50° C. The dark solution was cooled and then combined with 300 ml of dist. water, then 300 ml dichloromethane were stirred in, the mixture was suction filtered through Celite, the aqueous phase was separated off and extracted another three times with 50 ml of dichloromethane. The combined organic phases were washed with water, dried over sodium sulphate and evaporated down. The crude product thus obtained was dissolved in 250 ml dichloromethane, the solution was filtered through silica gel and then evaporated down. The residue was triturated with petroleum ether, suction filtered and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)([CH3:13])[CH2:11]OS1(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:12]([CH2:11][C:32]#[N:33])([CH3:13])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(CC[C@]2(C)COS(=O)(=O)N2C(=O)OC(C)(C)C)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CC[C@](C)(CC#N)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a stirred solution of (R)-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-2,2-dioxo-2λ*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (174 mg, 0.40 mMol) in DMF (5 ml) is added sodium cyanide (94 mg, 1.91 mMol). The mixture is stirred at RT for 25 hours. Additional sodium cyanide (37 mg, 0.76 mMol) is added and the mixture is stirred at RT for 18 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted twice with AcOEt. The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 5% AcOEt in toluene gives the title compound as a colourless oil.
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[O:3]=[C:4]1[O:1][C@H:7]([C@H:5]([CH2:4][OH:3])[OH:6])[C:7]([OH:8])=[C:5]1[OH:6]
Reactant: [OH-]
Reactant: OCC(O)CO
Agent: [Na+]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 10.5 h

Procedure:
The fourth and final fermentation step is performed in a 15000-liter vessel with the inoculation from step no 3. The fermentation is performed at 37° C. for 9 to 12 hours with stirring and pH control. At the start of the fermentation the pH is 6.5. The pH control starts when the pH drops below 5.4 using a 20% sodium hydroxide solution. The pH control is set to pH 5.5. 100 mM glycerol is added in the final phase of the fermentation, just before the culture reaches the stationary phase. The fermentation is complete when the culture reaches the stationary phase, which can be seen by the reduction of the addition of the sodium hydroxide solution. Roughly 930 liters of the sodium hydroxide solution is added to the 10200 liters of media and 600 liters of inoculum during the fermentation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](O)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7](C(=O)C2C=CC=CC=2)[CH2:6]1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=C(c1ccccc1)C1CN(CCCO)CCC1(O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
When proceeding as described in Example 2, but replacing 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine (used as starting material in said example) by 1-(3-hydroxypropyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 80 g. thereof with benzene in the presence of aluminum chloride, 50 g. of 1-(3-hydroxypropyl)-4,4-diphenylpiperidine are obtained. The boiling point of said crude base is from 173° to 182° C./0.01 mm. Hg. Its hydrochloride has a melting point of 233° to 234.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][C:9]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15](C([O-])=O)[CH2:14]2)=[N:10][CH:11]=1.[ClH:22]>ClCCCl.O1CCOCC1>[ClH:22].[ClH:22].[NH:15]1[CH2:16][CH2:17][C@@H:13]([NH:12][C:9]2[N:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:21])=[N:7][CH:8]=2)[CH2:14]1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)[O-])C2)cn1
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate (10.50 g) in 1,2-dichloroethane (100 mL) was added a 4N HCl in dioxane (100 mL) and the mixture was stirred at 20-25° C. for 2 hours under nitrogen atmosphere to give a solid. The solid was collected by filtration to give methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (9.73 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[C:14]#[CH:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:15][C:14]#[CH:13]
Reactant: C#CCBr
Reactant: COC(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(C(=O)OC)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methyl 4-fluoro-3-hydroxybenzoate (20.0 mL, 0.118 mol) was dissolved in anhydrous acetone (450 mL), mixed with propargyl bromide (26.2 g, 0.177 mol) followed by the addition of powdered K2CO3 (32.4 g, 0.236 mol) and the reaction mixture was stirred overnight at room temperature. The reaction was filtered and the solvent was removed in vacuo. The residue was dissolved in diethyl ether, washed 4 times with H2O, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 25.5 g (100% yield) of a light peach coloured solid as the title compound (mp 60.5-61.5° C.). Mass spectrum (70 eV) m/z (relative intensity) 208 (27, M+), 207 (100), 193 (22), 177 (20), 149 (50), 82 (21), 81 (10).