Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[CH2:27][O:28][C:24]=2[CH:23]=1>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[NH:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[CH2:27][O:28][C:24]=2[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(c1)OCC2=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2c(c1)OCC2=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
54.7 ml (314 mmol) of diisopropylethylamine and 28.3 ml (188 mmol) of benzyl chloroformate are added to a solution of 23.42 g (157 mmol) of 6-amino-1-benzofuran-3(2H)-one in 400 ml of THF at 0° C. and the mixture is stirred at room temperature for 3 hours. Then a further 4.7 ml (31 mmol) of benzyl chloroformate are added, and the mixture is stirred overnight. The mixture is added to ice-water and extracted twice with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/ethyl acetate 5:1) affords 30.80 g (64% of theory) of the product as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([CH2:18][N:19]=[C:20]=[O:21])=[CH:16][CH:15]=1>>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:20]([NH:19][CH2:18][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:25])[F:24])=[CH:23][CH:22]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1ccc2cnccc2c1

Procedure:
Prepared from 6-aminoisoquinoline (Description 51) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 346 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1C=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([NH:44][S:25]([C:2]([F:1])([F:29])[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:26])=[O:27])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluoroctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.12 g (100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[C@@H:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:26][C@@H:27]([NH2:29])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: C[C@H](N)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@H](C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)-propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J=7.58 Hz, 1 H), 7.71 (d, J=7.33 Hz, 1 H), 7.67-7.60 (m, 1 H), 7.49 (t, J=7.33 Hz, 1 H), 7.42 (d, J=8.59 Hz, 1 H), 7.28-7.19 (m, 2 H), 6.07-5.83 (m, 1 H), 5.02 (brs, 2 H), 3.62 (s, 1 H), 3.56-3.46 (m, 2 H), 3.37 (s, 2 H), 3.28-3.11 (m, 4 H), 2.36 (s, 3 H), 0.92-0.80 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1nccs1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2cn3ccsc3n2)cc1
Reaction time: 16 h
Yield: 86 %

Procedure:
To a mixture of 2-aminothiazole (23.7 g, 0.23 mol) and 2-bromo-4′-fluoroacetophenone (alternatively named: 2-bromo-1-(4-fluorophenyl)-ethanone) (50 g, 0.23 mol) is added absolute ethanol (600 ml). The reaction is allowed to reflux with vigorous stirring for 16 hours. The reaction mixture is reduced to half its original volume in vacuo. The remaining liquid is poured onto ice and the solution made basic by the addition of ammonium hydroxide solution (30%). The resulting fine solid is filtered and washed with water. The dark yellow solid so obtained is dried in a vacuum oven at 50° C. to provide 6-(4-fluorophenyl)-imidazo[2,1-b]thiazole (43.0 g, 86%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[N:14][N:15]=2)[CH:5]=1.O.[OH-].[Na+].Cl>CO>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[O:12][C:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])=[N:15][N:14]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cc2nnc(-c3ccc(C#N)cc3)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2nnc(Cc3cccc(C(=O)O)c3)o2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Suspend of 3-[5-(4-cyano-phenyl)[1,3,4]oxadiazol-2-ylmethyl]-benzoic acid methyl ester (0.120 g, 0.376 mmol) in 4 mL of a 1:1 mixture of H2O:MeOH. Heat the mixture to 60° C., and add 10% aqueous solution of NaOH (0.28 mL, 0.70 mmol). Stir at 60° C. for 30 minutes, cool to room temperature and adjust the pH to 5 by the addition of a 2 N solution of HCl. Concentrate the mixture overnight under a stream of air, dilute crude residue with H2O and extract with methylene chloride. Wash the combined organic phase with brine, dry over anhydrous sodium sulfate and concentrate to provide 0.11 g 4% yield of 3-[5-(4-cyano-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-benzoic acid as a white solid.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13]>N1C=CC=CC=1.N1CCCCC1>[C:1]([C:3]1[S:7][C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1ccc(C=O)s1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1ccc(C=CC(=O)O)s1

Procedure:
A stirred solution of 5-cyano-2-thiophene carboxaldehyde (3.3 g) and malonic acid (2.5 g) in pyridine (35 ml) and piperidine (0.7 ml) was heated under reflux for 2 hours adding further malonic acid (1.3 g) after 1 hour. The solution was evaporated and the residue was stirred with M hydrochloric acid solution (100 ml) to give a pale solid which was washed with water and dried, m.p. ca 260° C. (subliming).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25](O)=[O:26])[C:19](=[O:28])[CH:18]=[CH:17]2>>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]([NH:7][C:4]1[S:5][CH:6]=[C:2]([Cl:1])[C:3]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1)=[O:26])[C:19](=[O:28])[CH:18]=[CH:17]2
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: O=C(O)Cn1c(=O)ccc2cc(Br)ccc21
Product: O=C(Cn1c(=O)ccc2cc(Br)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (115 mg, 573 umol) and 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid (135 mg, 479 umol) according to protocol A. HPLC purification gave 2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide. Method [7] Retention time 5.30 min by HPLC (M+=464, 466, and 468) are the major peak intensities. 1H NMR (300 MHz, CDCl3) δ 7.80 (m, 2H), 7.70 (s, 1H), 7.64 (dd, J=9.0 and 2.4 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.94 (d, J=9.3 Hz, 1H), 6.82 (s, 1H), 5.30 (s, 2H).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH3:37])[N:24]=1>>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[C:25]([CH3:37])[N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2nc(C)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 10 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7-dimethoxy-2-methylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 53.1 mg (yield: 10%) of Compound 80 was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1cncc(-c2ccc(S(C)(=O)=O)cc2)c1

Procedure:
4.5 g (20.8 mmol) of methyl 5-bromonicotinate and 5.0 g (25.0 mmol) of 4-(methylsulphonyl)phenylboronic acid were reacted according to the General Method 1A. Yield: 1.4 g (24% of theory)
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[Cl:1][S:2]([NH:5][C:6](=[O:7])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 5 L round bottom flask was charged with chlorosulfonyl isocyanate [Aldrich, product #142662] (149 mL, 1.72 mol) and dichloromethane (1.5 L) and cooled using an ice bath to 2° C. tert-Butanol (162 mL, 1.73 mol) in dichloromethane (200 mL) was added dropwise at a rate so that the temperature did not exceed 10° C. The resulting solution was stirred at room temperature for 30-60 min to provide tert-butyl [chlorosulfonyl]carbamate.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[C:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].O>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7]1[C:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:9]([C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OC)c1OS(C)(=O)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Concentrated nitric acid (0.62 ml) was added dropwise to an ice cooled solution of methyl 3,4-dimethoxy-2-methanesulfonyloxybenzoate (1.94 g, 0.0067 mol) in acetic anhydride (3 ml) and the reaction stirred for 1 hour. Water (20 ml) was carefully added, and the resulting precipitate filtered and washed with further water. Drying under suction filtration gave the subtitle compound as a white solid (1.94 g, 86%). 1H-NMR (CDCl3): δ=3.34 (3H, s), 3.94 (3H, s), 4.00 (3H, s), 4.18 (3H, s), 7.68 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[N:36][CH:35]=[N:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:40][CH2:39][CH:38]([N:33]6[CH:37]=[N:36][CH:35]=[N:34]6)[CH2:43][CH2:42]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:31])[F:32])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: c1ncn(C2CCNCC2)n1
Product: O=C1N=C(N2CCC(n3cncn3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-[1,2,4]triazol-1-yl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-[1,2,4]Triazol-1-yl-piperidine following General Procedure B.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:42])[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34]CC6C=CC=CC=6)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C(O)(=O)C.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:42])[C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(CCOCc5ccccc5)CC4)cc2)CO3)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(CCO)CC4)cc2)CO3)CC1
Yield: 28.6 %

Procedure:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-[4-(2-benzyloxyethyl)-piperazin-1-yl]benzamide (150 mg, 0.27 mmol) was dissolved in acetic acid (10 mL) and palladium (10%) on carbon (12 mg) was added. Hydrogenation at room temperature and at atmospheric pressure for 14 h followed by filtration and evaporation of the solvent in vacuo gave 180 mg of a crude product. The residue was partitioned between methylene chloride (60 mL) and 2 M NH3 (5 mL) and washed with brine (5 mL). Drying (MgSO4) the solution and evaporation of the solvent in vacuo gave 120 mg of crude material. Purification by preparative TLC on silica using chloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent afforded 37 mg (29% yield) of the title compound as a white solid: mp 211-212° C.; EIMS (70 eV) m/z (relative intensity) 479 (8, M30 ); [α]22D−26° (c 0.26, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].CS([C:18]1[N:28]=[C:21]2[N:22]=[C:23]([CH3:27])[CH:24]=[C:25]([CH3:26])[N:20]2[N:19]=1)(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][C:18]2[N:28]=[C:21]3[N:22]=[C:23]([CH3:27])[CH:24]=[C:25]([CH3:26])[N:20]3[N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Reactant: OCCOc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(OCCOc3ccc(Cl)cc3)nc2n1

Procedure:
A mixture of 2-(4-chlorophenoxy)ethan-1-ol (4.0 g, 23.19 mmol) and tetrahydrofuran (40 mL) was added to a 200 mL RBF under a nitrogen atmosphere with a magnetic stirring bar. Sodium hydride (60% dispersion in mineral oil) (1.26 g, 31.62 mmol) was added portion-wise (4×˜315 mg) over 10 minutes (Effervescence). The reaction was stirred for 10 minutes before 2-methanesulfonyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (4.76 g, 21.08 mmol) was added portion-wise (5×˜0.95 g) (Effervescence). Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. 2-Methanesulfonyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine elutes with retention time of 1.3 min, 2-(4-chlorophenoxy)ethan-1-ol elutes with retention time of 4.5 min, and the title compound elutes with retention time of 5.7 min. A precipitate is visible after 5 minutes of reaction. An additional portion of tetrahydrofuran (10 mL) was added to aid stirring. After 30 minutes the reaction was concentrated and then partitioned between dichloromethane (100 mL) and water (50 mL). The aqueous layer was extracted once more with dichloromethane (100 mL), and the combined organic layer was dried (Na2SO4), filtered, and concentrated. To a mixture of the crude material in 1% methanol in dichloromethane (60 mL), silica gel (10 g) was added, and the mixture swirled for 10 minutes. The silica gel was removed by filtration, rinsed with dichloromethane (100 mL), and the organic solvent was concentrated under reduced pressure. The solid was dissolved in warm ethanol (125 mL) and water (13 mL), and allowed to cool overnight. Crystalline material was isolated by filtration, rinsed with ethanol:water (10:1) (110 mL) and allowed to dry. A light pink color remained. The solid was then dissolved in 2% methanol in dichloromethane (30 mL), and to this mixture, silica gel (5 g) was added and swirled for 20 minutes. The silica gel was removed by filtration through a plug of fresh silica gel (2 g), rinsed with 2% methanol in dichloromethane (50 mL), and the organic solvent was concentrated under reduced pressure. The solid was dissolved in warm ethanol (95 mL) and allowed to cool overnight. An off-white crystalline material was isolated by filtration, rinsed with ethanol (75 mL), and dried to afford the title compound as an off white solid (4.22 g, 62% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.34 (d, 2H), 7.09 (s, 1H), 7.02 (d, 2H), 4.67 (t, 2H), 4.36 (t, 2H), 2.63 (s, 3H), 2.52 (s, 3H). EM (calc.): 318.1; MS (ESI) m/e: 319.2 (M+H)+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[CH3:6][O:7][CH2:8][CH:9]=O.C1CCCCC1>O>[CH3:6][O:7][CH2:8][CH:9]1[O:5][CH2:1][CH2:2][CH2:3][O:4]1
Reactant: COCC=O
Reactant: OCCCO
Solvent: C1CCCCC1
Solvent: O
Product: COCC1OCCCO1
Yield: 89 %

Procedure:
A mixture of 380 g (5 moles) of 1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb® AC 10 (Bayer Aktiengesellschaft) under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 587 g (89% yield) of 2-methoxymethyl-1,3-dioxane having a boiling range of 104° to 115° C./150 mbar were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[N+:14]([O-])([O:16]C(=O)C)=[O:15].[N+]([O-])(O)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(Cl)n(-c2ccccc2)n1
Reactant: CC(=O)O[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cc1nn(-c2ccccc2)c(Cl)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 9.6 g (0.05 mole) of 5-chloro-3-methyl-1-phenylpyrazole and 25 ml of acetic anhydride was added at 10°C to a solution of acetyl nitrate prepared from 25 ml of 90% nitric acid and 10 ml of acetic anhydride. The solution was stirred 2 hours at 20°-30°C and carefully poured onto ice water. The solid was filtered off and washed with cold water. One recrystallization from ethanol gave long white needles of product.
Reaction SMILES: [N:1]([C@@H:4]([CH3:16])[CH2:5][C:6]1[CH:7]=[C:8]([N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:11]=1[CH3:12])=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][C@@H:4]([CH3:16])[CH2:5][C:6]1[CH:7]=[C:8]([N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(N(C)C)cc1C[C@H](C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C)C)cc1C[C@H](C)N
Yield: 84.8 %

Procedure:
To a solution of N-{3-[(2S)-2-azidopropyl]-4-methylphenyl}-N,N-dimethylamine (71 mg, 0.325 mmol) in 10 mL of EtOAc was added Pd/C (30 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h. The catalyst was removed by filtration through celite, then passed through silicagel plug eluting first with EtOAc (10 mL), then MeOH/EtOAc/NH4OH 20:75:5 (20 mL). The fraction with product was evaporated to give N-{3-[(2S)-2-aminopropyl]-4-methylphenyl}-N,N-dimethylamine (53 mg, 85%) as pale yellow oil. ESI-MS: m/z (MH+) 193.1. 1H NMR (300 MHz, CDCl3): δ 7.02 (m, 1H), 6.57 (m, 2H), 3.16 (m, 1H), 2.90 (s, 6H), 2.44-2.74 (m, 2H), 2.22 (s, 3H), 1.48 (s, 2H), 1.14 (d, J=6.42 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18])[CH2:11][CH2:10]1.O.[NH2:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:22])[CH2:16][C:17]([NH:24][NH2:25])=[O:18])[CH2:11][CH2:10]1
Reactant: NN
Reactant: CCOC(=O)CC(C)N1CCN(c2ccccc2OC)CC1
Solvent: O
Solvent: CCO
Product: COc1ccccc1N1CCN(C(C)CC(=O)NN)CC1
Yield: 76 %

Procedure:
A solution of ethyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanoate D11 (2.75 g, 8.97 mmol) and hydrazine monohydrate (2.7 g, 53.85 mmol) in ethanol (40 mL) was refluxed for 48 hrs. The solvent was evaporated under reduced pressure, toluene (50 mL) was added and the solvent was evaporated and the resulting light yellow oil was triturated with 50% AcOEt in hexane (10 mL). The resulting white solid was filtered, washed with hexane and dried to afford 2 g (76%) 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanohydrazide D12.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 900 mg of 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide, 423.8 mg of methanesulfonyl chloride, and 393.6 mg of triethylamine in 32 ml dichloromethane give [1-(5-carbamoyl-4-{1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.