Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[NH2:15])=[O:5])C.C([O-])=O.[NH4+].Cl.[CH:21]([NH2:23])=O>>[N:15]1[C:7]2[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[C:6]=2[C:4]([OH:5])=[N:23][CH:21]=1
Reactant: CCOC(=O)c1c(N)[nH]c2cnccc12
Reactant: NC=O
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Product: Oc1ncnc2[nH]c3cnccc3c12
Temperature: 170 °C

Procedure:
A mixture of 2-Amino-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester (1.80 g, 8.8 mmol) and ammonium formate (0.62 g, 9.8 mmol) in formamide (10 mL) was heated at 170° C. for 18 hours. 1 M HCl was added to the cooled reaction mixture and the resulting suspension was filtered to remove insolubles. The filtrate was then adjusted to pH 7 with saturated sodium bicarbonate solution. The resulting precipitate was collected by filtration and dried to a constant weight in a vacuum oven to give the title compound (0.74 g, 4.0 mmol). 1H NMR (DMSO) δ 12.5 (s, br), 8.83 (1H, s), 8.37 (1H, d, J=4.0), 8.26 (1H, s), 7.89 (1H, d, J=4.0); LC-MS (1) Rt 0.75 min; m/z 185 (ES−).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: COCCOCCOCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl carbonate. This was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxycarbonyloxy}-ethyl ester as a white solid. LCMS (ES+) m/z calcd. for C41H48Cl2F2N3O10 [(M+H)+]: 850, found: 850.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[N:14][C:10]=2[CH:9]=1)(O)=[O:6]>C1C=CC=CC=1>[Cl:3][C:5]([C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[N:14][C:10]=2[CH:9]=1)=[O:6]
Reactant: COC(=O)Nc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)Nc1nc2cc(C(=O)Cl)ccc2[nH]1
Temperature: 23 °C

Procedure:
7.4 mL (12.069 g, 101.4 mmol) thionyl chloride and 1.80 g (7.66 mmol) methyl 5-carboxy-1H-benzimidazole-2-carbamate in 37 mL dry benzene were heated to reflux under argon for 3.5 hours. The mixture was then cooled to 23° C. and the solvent and excess thionyl chloride were distilled under reduced pressure. The resulting brown solid was stored under vacuum to remove all traces of thionyl chloride and used in the following Examples without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOCC1CN(C(=O)OC(C)(C)C)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCOCC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of 4-hydroxy-3-methoxymethoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Example 38, 9.1 mmol, 2.5 g) in 50 mL of DCM was added Dess-Martin reagent (10.8 mmol, 4.6 g). The mixture was stirred at room temperature for 2 h, then washed with saturated sodium bicarbonate solution, brine, dried, evaporated, the resulting residue was chromatographed with 9:1 hexane/EtOAc afforded 3-methoxymethoxymethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.2 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:26][NH:27][CH3:28].CC(=O)CC>C(OCC)(=O)C.CCCCCC>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]([CH3:28])[CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CNC
Solvent: CCCCCC
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCCc1oc(N(C)C)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), an aqueous solution of dimethylamine (50%, 1.0 ml) and 2-butanone (10 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was concentrated, the residue obtained was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-dimethylamino-5-[3-(2-methoxyphenoxy)propyl]oxazole was obtained as an oil (348 mg, 90%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction. Crystallization from acetone-hexane gave pale yellow prisms. Melting point 67-68° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[CH:9]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Ic1cccnc1
Product: Fc1ccc(C#Cc2cccnc2)cc1
Yield: 40.6 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 3-iodopyridine (153 mg, 0.75 mmol) and 1-ethynyl-4-fluorobenzene (100 mg, 0.83 mmol) to give the title compound (60 mg, 40%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[OH-].[CH2:27]([N+:43]([CH3:46])([CH3:45])[CH3:44])[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][CH3:42]>O>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O-:20])=[O:19])(=[O:16])=[O:15].[CH2:27]([N+:43]([CH3:46])([CH3:44])[CH3:45])[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][CH3:42]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)[O-])cc(N2CCCC2)c1Oc1ccccc1

Procedure:
In a similar manner to Example 10, piretanide can be reacted with cetyltrimethylammonium hydroxide in water to yield cetyltrimethylammonium 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ncc(C(F)(F)F)cn3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(Nc2ccc([C@H]3CNCCO3)cc2)nc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
To a stirred solution of (S)-2-[4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (87 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.77 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford ((S)-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine (41 mg, 62%) as a white solid. MS (ISP): 325.3 ([M+H]+).
Reaction SMILES: C(S(C1C=CC(CNC(C2C=C3CN[C@@H](C(C)C)C3=NC=2)=O)=CC=1)(=O)=O)C.[CH2:28]([S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][NH:40][C:41]([C:43]2[CH:44]=[C:45]3[CH2:51][N:50](C(OC(C)(C)C)=O)[C@@H:49]([CH:59]([CH3:61])[CH3:60])[C:46]3=[N:47][CH:48]=2)=[O:42])=[N:37][CH:38]=1)(=[O:32])=[O:31])[CH3:29]>>[CH2:28]([S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][NH:40][C:41]([C:43]2[CH:44]=[C:45]3[CH2:51][NH:50][C@@H:49]([CH:59]([CH3:60])[CH3:61])[C:46]3=[N:47][CH:48]=2)=[O:42])=[N:37][CH:38]=1)(=[O:31])=[O:32])[CH3:29]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)nc1
Agent: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)nc1
Reaction time: 0.02 h

Procedure:
Procedure same as that for (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, using tert-butyl(S)-3-(((5-(ethylsulfonyl)pyridin-2-yl)methyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as a starting material. LC-MS tR=0.48 min in 1 min chromatography, MS (ESI) m/z 389.3 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 9.06 (dd, J=0.8 Hz, 2.0 Hz, 1H), 8.93 (t, J=0.8 Hz, 1H), 8.19 (dd, J=2.0 Hz, 8.4 Hz, 1H), 8.01 (t, J=0.8 Hz, 1H), 7.56 (dd, J=0.8 Hz, 8.0 Hz, 1H), 7.52 (s, 1H), 4.89 (d, J=5.2 Hz, 2H), 4.35 (dd, J=1.2 Hz, 4.0 Hz, 1H), 4.32 (d, J=0.8 Hz, 2H), 3.17 (q, J=7.6 Hz, 2H), 2.34-2.26 (m, 1H), 1.33 (t, J=7.6 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[N:19][C:18]=1[O:24]C)=O)(C)(C)C.C[Si](Cl)(C)C.O>C(#N)C>[Cl:23][C:21]1[CH:22]=[C:17]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:18](=[O:24])[NH:19][N:20]=1
Reactant: COc1nnc(Cl)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CC#N
Product: O=c1[nH]nc(Cl)cc1-c1cc2ccccc2[nH]1

Procedure:
2 g of 2-(6-chloro-3-methoxy-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester is treated for 16 h at 85° C. with 2.76 g of KI and 1.8 g of trimethylsilylchloride in 200 ml acetonitrile. On completion of the reaction the reaction solution is poured into water and the precipitated product is isolated by filtration. Yield: 1.33 g. LC-MS (ES+) 246 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]2)=[C:4]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1>[CH2:42]([O:41][C:39](=[O:40])[O:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:13]1)[CH3:43]
Reactant: O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1S,4R)-4-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enol (3.00 g, 6.95 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry THF (100 mL) is added followed by dry pyridine (1.10 g, 13.90 mmol). Ethyl chloroformate (3.02 g, 27.80 mmol) is added slowly and the reaction mixture is stirred at room temperature for 4 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 mL) and 10% citric acid (200 mL). The organic layer is washed with water (150 ml) and brine (150 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, iso-hexane/ethyl acetate 2:1). 1H nmr (CDCl3, 400 MHz); 7.70 (br s, 1H), 7.35-7.15 (m, 10H), 6.35 (m, 1H), 6.15 (m, 1H), 5.80 (m, 1H), 5.65 (m, 2H), 4.35 (t, 1H), 4.25 (m, 2H), 4.20 (q, 2H), 3.10 (m, 1H), 1.95 (d, 1H), 1.30 (t, 3H), MS (ES+) m/e 504 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:30])[C:10]([CH3:29])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18](C(OC(C)(C)C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[CH:16]4)[C:10]([CH3:29])=[C:9]([F:30])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reaction time: 4.5 h
Yield: 17.3 %

Procedure:
A mixture of 1,1-dimethylethyl 5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazole-1-carboxylate (Example 59) (0.46 g) in a solution of hydrogen chloride in dioxan (4M, 7 ml) was stirred at room temp. under nitrogen for 4.5 h. The solvent was evaporated and the residue was partitioned between dichloromethane (20 ml) and aqueous sodium hydroxide (2M, 20 ml). The organic layer was separated using a hydrophobic filter tube, the solvent was evaporated and the residue was purified on a Varian Bond-Elut SPE cartridge (silica, 10 g) eluting with chloroform:methanol (100:0 to 98:2) to give the title compound (0.06 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[NH2:19])C.[OH-].[Na+].Cl>C1COCC1>[NH2:19][C:10]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)CCCCc1cc(OC)c(OC)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(N)c(CCCCC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(2-amino-4,5-dimethoxy-phenyl)-pentanoic acid ethyl ester (Example 122, Step B) (0.1 g, 0.35 mmol) in THF (3 mL) was added NaOH (2 M, aqueous) (3 mL) and the mixture was stirred vigorously at RT for 12 h. The reaction was neutralized by the slow addition of HCl (2 N, aqueous) followed by removal of the THF under reduced pressure. The aqueous mixture was extracted with CH2Cl2 (3×10 mL) and the organic layers were combined, washed with brine, dried with MgSO4, and filtered. Concentration under reduced pressure afforded the title compound as a brown solid that was carried on without purification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[N:18]#[C:19][NH2:20].[Na]>>[O:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:2]3[O:1][C:19]([NH2:20])=[N:18][CH2:3]3)=[CH:7][CH:8]=2)[CH2:13][CH2:14]1
Reactant: N#CN
Reactant: c1cc(C2CCOCC2)ccc1OCC1CO1
Agent: [Na]
Product: NC1=NCC(COc2ccc(C3CCOCC3)cc2)O1

Procedure:
The title compound was prepared from 4-(4-oxiranylmethoxy-phenyl)-tetrahydropyran and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:9][OH:10])=[N:6][CH:7]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:11])=[N:9][OH:10])=[N:6][CH:7]=1
Reactant: ON=Cc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Br)cn1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
5-Bromopyridine-2-carbaldehyde oxime (49.5 g, 246.3 mmol) was dissolved in DMF (150 ml) followed by addition of N-chlorosuccinimide (39.5 g, 295.5 mmol). HCl gas was then bubbled in the solution for 20 seconds to initiate the reaction, which was then allowed to stir for 1 hr. The reaction was poured into distilled water (1 L) and the precipitate was collected by vacuum filtration. The filter cake was washed with distilled water (2×500 ml) and then dried overnight in a vacuum oven at 60° C. (−30 inches Hg) to yield the product as a white powder (55 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:27])[NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[O:26])[CH3:25])[N:23]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:24]([C:22]1[N:23]=[C:19]([NH:18][C:17](=[O:27])[C@@H:8]([NH2:7])[C@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[S:20][CH:21]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)c1csc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
[(1S,2S)-1-(4-Acetyl-thiazol-2-ylcarbamoyl)-2-phenyl-propyl]-carbamic acid tert-butyl ester (2.8 g, 6.25 mmol) was dissolved in dichloromethane (42 mL) in an ice bath. Trifluoroacetic acid (35 mL) was added. After 30 minutes, the reaction mixture was evaporated and the residue was precipitated with hexanes/ether. The mixture was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave (2S,3S)-N-(4-acetyl-thiazol-2-yl)-2-amino-3-phenyl-butyramide (1.9 g, 95%) as a white solid.
Reaction SMILES: C([N:8]1[C:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])O)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.O.[ClH:24].[H][H]>[Pd].C(O)C>[ClH:24].[CH3:22][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:13][C:12]1[N:8]=[CH:9][NH:10][CH:11]=1
Reactant: Cc1cccc(C(O)c2cncn2Cc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cccc(Cc2c[nH]cn2)c1C
Temperature: 3 °C
Reaction time: 2 h

Procedure:
1-Benzyl-5-(2,3-dimethylphenylhydroxymethyl)imidazole (20 kg), water (225 l), 30% HCl (20 l), ethanol (5 l) and palladium on charcoal 10% (4.4 kg) are charged. The mixture is stirred under 2.2 bar overpressure of hydrogen at 75±5° C. for 24 hours. The reaction mixture is filtered at 45±3° C. and the filter cake is washed with water (30 l). 170 l of water is distilled off under reduced pressure and 30% HCl (8 l) is added. The solution is cooled to 3±3° C. during 2 h. The solution is seeded with crystals of detomidine HCl at 40±5° C., 30±5° C., 20±5° C. and at 10±5° C., until the crystallization starts. The mixture is agitated for two hours. The crystalline compound is collected by centrifugation and washed with toluene. The crude product and water (250 l) are charged. The solution is heated to about 50° C. and stirred for 1 hour. The solution is cooled to 10° C. during 1.5 hour. The solution is filtered and 180 l of water is distilled off under vacuum. 30% HCl (20 l) is added and the solution is warmed to 60° C., and then cooled to 3±3° C. during 2 hours. The solution is seeded as above until the crystallization starts and agitated for two hours. The crystalline compound is collected by centrifugation and washed with toluene. The product is dried under vacuum at 39±5° C. for 20 hours, at 61±5° C. for 6 hours and at 85±5° C. for 16 hours. The yield is 10.5 kg (78%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[CH:6]([CH2:17][NH2:18])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH3:3].[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][C:33](Cl)=[O:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].S(Cl)(Cl)=O.COC1C=C(CC(O)=O)C=CC=1OC>C1(C)C=CC=CC=1.C(Cl)Cl.O>[CH2:2]([O:4][C:5](=[O:19])[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:17][NH:18][C:33]([CH2:32][C:26]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:34])[CH3:3]
Reactant: CCOC(=O)C(CN)c1ccc(OC)c(OC)c1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: COc1ccc(CC(=O)O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1

Procedure:
A mixture of 289 g of alpha-(aminomethyl)-3,4-dimethoxybenzeneacetic acid ethyl ester hydrochloride, 1000 ml of methylene chloride and 1000 ml of water was cooled to 0° and adjusted to pH 9.0 with 4N sodium hydroxide. A solution of 1000 ml of methylene chloride and 3,4-dimethoxyphenyl acetic acid chloride [previously prepared by the action of 400 ml of thionyl chloride on 215 g of 3,4-dimethoxyphenyl acetic acid in 500 ml of toluene at 50° for 1 hour and evaporation to dryness] was added concurrently with 4N sodium hydroxide maintaining a pH of 7.0-8.0. Upon completion of the acid chloride addition, the pH was maintained at 9.0 for 1 hour followed by acidification to pH 1.0 with 6N hydrochloric acid. The layers were separated and the aqueous layer extracted once with methylene chloride. The combined organic layers were washed once with exceess saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo to give 430 g of 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[N:8]3[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]23)=[O:27])=[CH:21][CH:20]=1
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CN1C(=O)N2C(=NC1(C)C)N(C(=O)Nc1ccc(Cl)cc1)c1ccccc12

Procedure:
The procedure of Example 10 was used to prepare the title compound from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and 4-chlorophenyl isocyanate. The confirmatory elemental analysis for the product, mp 206°-211° C., is shown in Table III.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[CH:30]([NH:33][NH2:34])([CH3:32])[CH3:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:33]([CH:30]([CH3:32])[CH3:31])[N:34]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: CC(C)NN
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C(C)C

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with isopropylhydrazine hydrochloride (CAS Reg. No. 16726-41-3) to give the title compound as yellow solid. MS (ESI): m/z=460.3 [M+H]+.