Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][C:17](=O)[C:18]4[CH2:19][S:20][N:21]=[C:22]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40].ClC(Cl)C.[CH3:45][O:46][C:47]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:48]=1[CH2:49][NH2:50].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH3:45][O:46][C:47]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:48]=1[CH2:49][NH:50][CH:17]1[C:18]2[CH2:19][S:20][N:21]=[C:22]([N:23]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:13]3=[N:12][N:11]([CH2:10][C:5]4[C:4]([CH3:40])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[N:39]=[C:15]([C:14]=23)[CH2:16]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (170 mg), dichloroethane (2 mL), acetic acid (0.034 mL) and 2,4-dimethoxybenzylamine (0.073 mL) was stirred at room temperature for 10 minutes. Then, sodium triacetoxyborohydride (126 mg) was added and the mixture was stirred for two hours. Sodium triacetoxyborohydride (63 mg) was added to the reaction mixture, followed by further stirring for one hour. Methanol (three drops) was added dropwise to the reaction mixture, and then the mixture was separated with chloroform and a 0.5 N sodium hydroxide solution. The aqueous layer was extracted with chloroform, and then the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (108 mg, 50%) as an oil.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25](=[O:27])[CH3:26]>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:26][C:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)=[O:27])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(C=Cc1ccc(-c2ccccc2)cc1)c1ccc2ccccc2c1

Procedure:
Synthesised according to example 1.59.1 using biphenyl-4-carbaldehyde (5.0 g, 29.3 mmol) and 1-(naphthalen-2-yl)ethanone (5.35 g, 29.3 mmol); yellow solid; yield: 7.80 g (79%);
Reaction SMILES: [NH2:1][C:2]1[N:28]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:26][CH3:27])[N:9]=[CH:10][C:5]=2[C:4](=[O:34])[C:3]=1[C:35]([NH2:37])=[O:36].CC[Cl:40]>ClCCl.CO.CCOCC>[ClH:40].[NH2:1][C:2]1[N:28]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:26][CH3:27])[N:9]=[CH:10][C:5]=2[C:4](=[O:34])[C:3]=1[C:35]([NH2:37])=[O:36]
Reactant: CCCl
Agent: CCC1CCN(c2ccc(Nc3ncc4c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c4n3)c(OC)c2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.25 g (0.50 mmol) of the product prepared in step 19.3 in 10 mL of a dichloromethane/methanol mixture (4/1) are added 2 mL (2 mmol) of 1.0 M hydrochloric ether. The mixture is stirred for 10 minutes at room temperature and is then diluted with ether. The precipitate is drained by suction, rinsed with ether and with pentane, and dried under vacuum. 0.28 g of the expected product is obtained in the form of a yellow solid. Yield (dihydrochloride)=96%. m.p.=200°C. (decomposition). M+H+=510.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>>[CH3:26][C:27]1[N:28]=[C:29]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[S:30][CH:31]=1
Reactant: Cc1cscn1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCOCC4)n3)c2n1
Product: Cc1csc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O)CCOCC3)n2)n1

Procedure:
This is prepared from 7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine and 4-methylthiazole by the method of Example 38.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]#[N:27])[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1)=O>>[OH:3][N:2]=[CH:4][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]#[N:27])[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Reactant: NO
Agent: Cl
Product: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=NO)ccn23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using hydroxylamine hydrochloride (57 mg, 0.82 mmol) and 3-[3-(7-formylimidazo[1,2-α]pyridin-3-yl)phenyl]thiophene-2-carbonitrile (90 mg, 0.27 mmol) to afford a white crystalline solid (77 mg, 82%), essentially as a single geometric isomer, m.p. >230° C. 1H NMR (360 MHz, d6-DMSO) δH 7.27 (1H, dd, J 1 and 7), 7.70-7.82 (3H, m), 7.91 (1H, s), 8.03 (1H, s), 8.17 (1H, d, J 1), 7.90-7.95 (1H, m), 8.17 (1H, d, J 5), 8.31 (1H, s), 8.65 (1H, d, J 7), 11.53 (1H, s); m/z (ES+) 345 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[PH:11](=[O:14])([OH:13])[OH:12].[CH2:15]([C:17]([CH2:45][CH3:46])([CH:19](Br)[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:16].C(O)(=O)C>C(O)C>[PH:11](=[O:12])([OH:14])[OH:13].[CH2:45]([C:17]([CH2:15][CH3:16])([CH:19]([O:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:46]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(C)(CC)C(ONC(=O)OC(C)(C)C)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 104.4 %

Procedure:
A stirred solution of t-butyl-N-hydroxycarbamate (0.25 g) in ethanol (10 ml) was treated with postassium hydroxide (0.10 g), then diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29) added. The mixture was allowed to stand for twenty hours, poured into ice-water, neutralized with a little acetic acid and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure to give crude diethyl 3-t-butoxycarbonylaminoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.14 g) as a colourless gum. NMR (CDCl3): δ 1.3(6H,t), 1.4(9H,s), 1.5-1.8(2H,m), 2.2-2.3(2H,m), 4.1(4H,m), 5.0(1H,t), 7.1(6H,m), 7.3(9H,m), 7.95(1H,s). M/S: M+ 620.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/C=C/C(OC)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:26])=O)C1C=CC=CC=1.CO.[BH4-].[Li+].CCCCCC.[C:37](OCC)(=[O:39])[CH3:38]>C1COCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[CH2:26][CH2:38][CH2:37][OH:39]
Reactant: COC(=O)/C=C/c1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: OCCCc1cc2ccccc2[nH]1
Temperature: 4 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
5-((E)-2-Methoxycarbonyl-vinyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.200 g, 0.573 mmol, 1 eq) was suspended in dry THF (10 mL) under Ar. Methanol (0.116 mL, 2.87 mmol, 5.0 eq) was added followed by cooling to 4° C. and the addition of lithium borohydride (1.40 mL of 2 M, 2.87 mmol, 5.0 eq). The reaction mixture was stirred and allowed to warm to room temperature, then heated to reflux. The reaction was followed by TLC (CH2Cl2/MeOH 9/1). After 24 hours, the reaction was quenched with brine and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with CH2Cl2/MeOH 9/1. 0.149 g (81% yield) of the indole-propanol was obtained as a white solid, with some contamination by the E-allylic alcohol (20%-30%).
Reaction SMILES: [Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([OH:20])=[CH:14][C:13]=2[O:12]1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:20][C:15]1[CH:16]=[CH:17][C:18]2[O:19][CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: FC(Cl)=CCCCCCCl
Reactant: Oc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(Cl)=CCCCCCOc1ccc2c(c1)OCO2
Yield: 63 %

Procedure:
Operating as described in Example 8 (part B), from 3 g of 1,7-dichloro-1-fluoro-1-heptene, 2.14 g of 3,4-methylendioxyphenol, 0.69 g of NaH and 30 ml of N,N-dimethylformamide there were obtained 2.8 g of the product of the above-cited formula, a colorless oil.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:13][C:14]1[CH:15]([OH:22])[CH2:16][C:17](=[CH2:21])[C:18]=1[CH2:19][CH3:20].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7]([O:22][CH:15]2[CH2:16][C:17](=[CH2:21])[C:18]([CH2:19][CH3:20])=[C:14]2[CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: C=C1CC(O)C(C)=C1CC
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=C1CC(OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)C(C)=C1CC
Reaction time: 8 h
Yield: 86.3 %

Procedure:
625 mg of (1R)-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride was added under ice-water cooling to a mixed solution of 400 mg of (RS)-2-methyl-4-methylidene-3-ethylcyclopent-2-en-1-ol, 5 mg of 2,6-di-t-butyl-4-methylphenol and 274 mg of pyridine in 6 ml of toluene. The reaction was continued at an ambient temperature for eight hours. The reaction solution was added to a 5% citric acid solution under ice-water cooling, and extracted three times with diethyl ether. The combined ether layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to yield 781 mg of (RS)-2-methyl-4-methylidene-3-ethyl-2-cyclopenten-1-yl (1R)-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (Compound No.5). Yield 82%. (Eluent: n-hexane/ethyl acetate=30/1, 2,6-di-t-butyl-4-methylphenol 0.1%) nD23 1.5251
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:16][C:17]([F:28])([F:27])[CH2:18]OS(C(F)(F)F)(=O)=O>CN(C=O)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[O:8][CH2:18][C:17]([F:28])([F:27])[F:16]
Reactant: Nc1ncnc(Cl)c1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc(Cl)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A reaction mixture of 4-Amino-6-chloro-pyrimidin-5-ol (500.00 mg; 3.44 mmol; 1.00 eq.), Cs2CO3 (1343.15 mg; 4.12 mmol; 1.20 eq.), and Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.59 ml; 4.12 mmol; 1.20 eq.) in DMF 2 ml was stirred at RT for overnight. lc-ms showed clean desired, worked up, purified by HPLC, collected title compound 610 mg, yield 78%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:53]4[CH2:54][CH2:55][N:50]([CH:47]([CH3:49])[CH3:48])[CH2:51][CH2:52]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCN(C(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 1-isopropylpiperazine (Oakwood) to give the title product. LC-MS (ES+) 775 [(M+H)+].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([C:10]#[N:11])[C:7]=2[CH:12]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].Cl>ClCCl.ClC(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([C:4]1[C:3]([OH:2])=[CH:12][C:7]2[C:8]([C:10]#[N:11])=[CH:9][C:6]=2[CH:5]=1)=[O:21]
Reactant: COc1ccc2c(c1)C(C#N)=C2
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
While stirring at from 20° to 30°, 7.96 g of 5-methoxybenzocyclobutene-1-carbonitrile in 40 ml of dichloromethane are added dropwise to a suspension of 26.6 g of aluminium trichloride in 60 ml of dichloromethane. Stirring is carried out for 30 minutes at from 20° to 30° and then, over a period of 15 minutes, 20.95 g of 2,6-dichlorobenzoyl chloride are added dropwise thereto and the whole is stirred for 4 hours at room temperature and then poured into a mixture of 500 g of ice-water and 10 ml of concentrated hydrochloric acid. Stirring is then carried out for 30 minutes, 200 ml of trichloromethane are added, the whole is vigorously shaken and the organic phase is separated off, washed several times with semiconcentrated hydrochloric acid, dried over magnesium sulphate, concentrated to dryness by evaporation and recrystallised from dichloromethane/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile is obtained having a melting point of 174°-175°.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:43])[C:12]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[CH:13][N:14]2[CH2:23][C:24]([NH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:25].CI>C(OCC)(=O)C.O>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:43])[C:12]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)=[CH:13][N:14]2[CH2:23][C:24]([N:26]([CH3:3])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:25]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)N(C)CCN3CCOCC3)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Sodium hydride (60% oil base, 61 mg, 1.4 mmol) was added to a DMF solution (2 ml) of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (580 mg, 1.16 mmol), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (230 mg, 1.62 mmol) was added thereto, and the thus-obtained mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-methyl-N-(2-morpholin-4-ylethyl)acetamide (440 mg, yield: 74%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[ClH:10].[O-2].[Mg+2:12]>O>[ClH:10].[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Mg+2:12]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 60 °C
Yield: 100 %

Procedure:
541 kg of L-aspartic acid are dispersed in 1016 l of demineralized water by stirring with heating to 60° C. 592 kg of a 25% by weight hydrochloric acid and then 164 kg of magnesium oxide as powder are added to this dispersion and stirred. After a clear solution has been obtained, it is filtered and spray dried in the manner described in Example 1, resulting in magnesium L-aspartate hydrochloride in the form of a white powder in 100% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[CH:18]1([CH2:21][O:22][CH2:23][CH:24]=[C:25]2[CH2:31][CH:30]3[NH:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[CH2:20][CH2:19]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C.O>[CH:18]1([CH2:21][O:22][CH2:23][CH:24]=[C:25]2[CH2:26][CH:27]3[N:32]([CH2:2][CH2:3][CH2:4][N:5]4[C:14]5[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=5)[CH2:8][CH2:7][C:6]4=[O:17])[CH:30]([CH2:29][CH2:28]3)[CH2:31]2)[CH2:20][CH2:19]1
Reactant: C(COCC1CC1)=C1CC2CCC(C1)N2
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=C1CCc2cc(F)c(F)cc2N1CCCN1C2CCC1CC(=CCOCC1CC1)C2
Temperature: 50 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (78 mg, 0.30 mmol), 3-(2-cyclopropylmethoxyethylidene)-8-aza-bicyclo[3.2.1]octane (42 mg, 0.2 mmol), NaI (75 mg, 0.50 mmol), and K2CO3 (69 mg, 0.50 mmol) in CH3CN/DMF(1 ml, 50:50). The reaction was shaken at 50° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography followed by flash column chromatography (SiO2; EtOAc/MeOH, 90:10) to yield the title compound as an oil (46 mg, 0.11 mmol, 53%). 1H NMR (CDCl3) d 7.14 (dd, J=6.8, 12.4 Hz, 1H), 6.95-6.88 (m, 1H), 5.40 (t, J=6.6 Hz, 1H), 3.99-3.86 (m, 4H), 3.33-3.25 (m, 2H), 3.21 (d, J=6.8 Hz, 2H), 2.8 (t, J=6.8 Hz, 2H), 2.62-2.53 (m, 3H), 2.48 (t, J=6.8 Hz, 2H), 2.25 (br s, 1H), 1.95-1.74 (m, 5H), 1.58-1.36 (m, 2H), 1.08-0.96 (m, 1H), 0.56-0.44 (m, 2H), 0.22-0.08 (m, 2H); 13C NMR (CDCl3) d 166.5, 146.2 (dd, J=13, 243 Hz), 142.4 (dd, J=13, 243), 134.2, 133.4 (br), 120.7 (br), 119.4 (br), 113.3 (d, J=18 Hz), 102.1 (br), 71.8, 63.0, 56.7, 56.4, 45.3, 38.0, 37.7, 30.9, 28.6, 23.9, 23.6, 23.0, 22.0, 7.7, 0.0; HPLC-MS (ammonium acetate) [M+H]+=398.21.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[OH:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1>>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][O:17][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OCc1cccs1
Product: O=C(OCc1cccs1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with 2-hydroxy methyl thiophene.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>CS(C)=O>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cl)nc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(Cl)nc1
Temperature: 90 °C

Procedure:
25.6 g of sodium cyanide (0.522 mol) are dissolved in 123 g of dimethyl sulfoxide, the mixture is heated to 90° C. and 68.9 g (0.43 mol) of 2-chloro-5-chloromethylpyridine are introduced in portions. During this, the temperature rises to 130° C. The mixture is allowed to cool to room temperature, poured into water and extracted using ether. The solvent is removed and the crude product is distilled at 1.0 mbar (130°-135° C.). M.p.: 80° C. Yield: 41.1 g (63% of theory).
Reaction SMILES: C([NH:14][CH:15]([P:26]([OH:28])[OH:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([P:26]([OH:28])[OH:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1
Reactant: OP(O)C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)c1ccccc1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC(Cc1c[nH]c2ccccc12)P(O)O

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-2-(indol-3-yl)-ethanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-2-(indol-3-yl)-ethanephosphonous acid.
Reaction SMILES: [C:1]1([C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:34]>C(OCC)C>[C:23]12([C:1]3[CH:2]=[CH:3][C:4]([C:7]4[N:11]=[CH:10][N:9]([C:12]5[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=5)[N:8]=4)=[CH:5][CH:6]=3)[O:34][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C4=CCCCC4)cc3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C45CCCCC4O5)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
To a solution of 3-(2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB10) (3.11 g, 8.07 mmol) in diethyl ether (60 mL) was added meta-chloroperoxybenzoic acid (70%; 2.79 g, 11.3 mmol) slowly at 0° C. The reaction was stirred and allowed to gradually warm to room temperature, then stirring was continued for 18 hours. The solution was diluted in diethyl ether, washed with sodium bicarbonate, extracted with diethyl ether, washed with water, and extracted again with diethyl ether. The organics were dried, filtered, and concentrated providing the title compound as a white solid (2.5 g, 77%) which was used without further purification: 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.20-8.11 (m, 2H), 7.84-7.77 (m, 2H), 7.52-7.46 (m, 2H), 7.39 (dt, J=8.0, 1.0 Hz, 2H), 3.12 (dd, J=3.1, 1.7 Hz, 1H), 2.34 (ddd, J=14.9, 8.5, 5.3 Hz, 1H), 2.09-1.95 (m, 2H), 1.74-1.45 (m, 4H), 1.42-1.28 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 402 ([M+H]+).