Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.B(F)(F)F.[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([S:21]([N:24]2[CH:25]=[CH:26][CH:27]=[C:28]2[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: FB(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 4-fluorobenzoylchloride (1.74 g, 11 mmol) in dichloromethane (2 ml) was added dropwise a solution of boron trifluoride diethyletherate (3.4 ml, 27.6 mmol) in dichloromethane (20 ml). The mixture was stirred for 10 minutes at room temperature. Subsequently, to the mixture was added dropwise a solution of 1-benzenesulfonylpyrrole (1.9 g, 9.2 mmol) in accordance with a method described in Example 8 (1) in dichloromethane (5 ml). The mixture was stirred for 12 hours. The reaction mixture was poured into ice-water and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crude crystal was recrystallized from isopropylether to give 1-benzenesulfonyl-2-(4-fluorobenzoyl)pyrrole (1.0 g) as a crystal. Yield: 19.8%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([OH:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH:25](O)[CH3:26])[CH2:21][CH2:20]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([O:13][CH2:26][CH2:25][N:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(O)N1CCOCC1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(O)c2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCN3CCOCC3)c2)n1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 5-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO2007/091152, which is incorporated herein by reference; 200 mg, 0.75 mmol), 2-N morpholino ethanol (137 μL, 1.13 mmol) and Ph3P (394 mg, 1.50 mmol) in THF (7.5 mL) at 0° C. was added DEAD (236 μL, 1.50 mmol). After 1 h, the reaction mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound (228 mg, 80%). LCMS (Method 3): Rt 2.28 min, m/z 379 [MH+].
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH:30]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][S:34]([N:3]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[O:11])[CH2:4]2)(=[O:36])=[O:35])[CH2:32][CH2:31]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: O=S(=O)(Cl)CC1CC1
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(=O)(=O)CC4CC4)C3)cnc21

Procedure:
1-(1-Cyclopropylmethanesulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and cyclopropyl-methanesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:29]1([CH2:38][C:39](O)=[O:40])[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:39](=[O:40])[CH2:38][N:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.29 (s, 0.6H), 11.28 (s, 0.4H), 9.20 (brs, 1H), 8.41–8.40 (m, 1H), 8.07–7.97 (m, 2H), 7.33 (s, 0.6H), 7.26 (s, 0.4H), 4.67 (s, 1.2H), 4.48 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.06 (s, 1.2H), 3.58 (t, 1.2H), 3.46–3.40 (m, 2H), 3.28 (t, 0.8H), 1.75 (s, 3H), 1.24 (t, 1.2H), 1.18 (t, 1.8H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.S1(CCCC1)(=O)=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17](=[CH:21][CH:22]=1)[C:18]([OH:20])=O>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:17]([C:18](=[O:20])[NH:3][C:2](=[O:1])[N:23]2[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CNc1cc(Cl)ccc1C(=O)O
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
A total of 128 g of potassium cyanate and 144 g of hydrogen chloride are metered into 700 g of sulfolane at 15-20° C. over a period of 5 hours. For this, 14.4 g of hydrogen chloride are first passed in and 12.8 g of potassium cyanate are then added; this operation is repeated 10 times, until the entire amount of hydrogen chloride and potassium cyanate has been added. 117 g of 4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid are then added at 45-50° C. in the course of 2 hours. The mixture is subsequently stirred for 15 minutes. The suspension is filtered and the residue is washed free from sulfolane and salt with water. After drying, 121 g (95%) of ethyl 1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate are obtained.
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35][C:36](=O)[CH2:37]Cl)(=[O:33])[CH3:32]>CC(C)=O>[C:31]([O:34][CH2:35][C:36]1[CH2:37][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:6])(=[O:33])[CH3:32]
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCc1ccc(OC)cc1
Reactant: CC(=O)OCC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(COC(C)=O)CSC=N2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 105.4 %

Procedure:
To a stirring solution of p-methoxybenzyl α-thioformamido-diethylphosphonoacetate (114 mg., 0.3 mmole) in acetone (1.5 ml.) is added powdered potassium carbonate (124 mg., 0.9 mmole). The resulting mixture is stirred for 5 minutes at room temperature and under a nitrogen atmosphere, then treated with a solution of 1-acetoxy-3-chloro-2-propanone (48 mg., 0.32 mmole) in acetone (0.5 ml.). After having been stirred for 3 hours at room temperature, the mixture is filtered to remove the salts which are washed with acetone. The combined filtrate and washings are evaporated in vacuo to a dark oil. The residue is dissolved in carbon tetrachloride (6 ml.), washed with aqueous phosphate (1 ml. of 1M dipotassium phosphate + 2 ml. water) and water (2 × 3 ml.), dried over magnesium sulfate, and evaporated in vacuo to give crude p-methoxybenzyl 5-acetoxymethyl-6H-1,3-thiazine-4-carboxylate (106 mg.) as an organic oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(O)cc4)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(OC(C)=O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
N-(4-Hydroxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (47 mg) was dissolved in methylene chloride (6 ml), after the addition of triethylamine (2 ml), acetic anhydride (0.5 ml) was added, and the admixture was stirred at room temperature for 15 hours. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 35 mg of the title compound (yield: 68%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:11]1([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)c1ccc(C2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(C2CC2)cc1
Temperature: -70 °C

Procedure:
4-Cyclopropyl-benzoic acid ethyl ester (2.46 g, 13 mmol), and THF (250 mL) were combined under nitrogen and cooled in an IPA/dry ice bath to −70° C. Lithium aluminum hydride solution (20 mL, 20 mmol, 1.0M) was added dropwise. After 2 h excess lithium aluminum hydride was quenched by adding EtOAc dropwise. The reaction was warmed to 25° C., then the solvent was removed in vacuo. Water (200 mL) and a few drops of HCl (aq, 6N) were added. The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried with NA2SO4 and filtered. The filtrate was removed in vacuo and the remaining residue was purified by flash column chromatography (hexane:EtOAc 40:60) to give (4-cyclopropyl-phenyl)-methanol as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH2:8])=[O:6].[CH2:15]([N:19]=[C:20]=[S:21])[CH:16]([CH3:18])[CH3:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH:8][C:20]([NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[S:21])=[O:6]
Reactant: CC(C)CN=C=S
Reactant: COc1ccc(C(=O)NN)c(OC)c1
Solvent: CCO
Product: COc1ccc(C(=O)NNC(=S)NCC(C)C)c(OC)c1
Yield: 90 %

Procedure:
Ex-109B: A solution of 2,4-dimethoxy-benzoic acid hydrazide (Ex-109A, 1.0 g, 5.1 mmol) and isobutyl-isothiocyanate (0.70 g, 6.1 mmol) in ethanol (30 mL) was refluxed for 8 hours. The precipitate was filtered, washed with ethanol, dried in vacuo to afford 1-(2,4-dimethoxy-benzoyl)amino-3-isobutyl-thiourea (1.43 g). Additional product (0.1 g, 96% overall) was obtained by concentrating the mother liquid. 1H NMR (CDCl3) δ 10.71 (bs, 1H), 9.23 (bs, 1H), 8.03 (d, J=8.6 Hz, 1H), 6.98 (bs, 1H), 6.59 (dd, J=8.6, 2.6 Hz, 1H), 6.51 (d, J=2.6 Hz, 1H), 4.02 (s, 3H), 3.86 (s, 3H), 3.41 (dd, J=6.4, 6.6 Hz, 2H), 1.96–1.87 (m, 1H), 0.91 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:32]12[CH2:37][CH:36]1[CH2:35][NH:34][CH2:33]2.C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14]([N:34]2[CH2:35][CH:36]3[CH:32]([CH2:37]3)[CH2:33]2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Reactant: C1NCC2CC12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 5 h
Yield: 23.9 %

Procedure:
In absolute THF (15 mL) were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-formamide (200 mg, 0.45 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride salt (81 mg, 0.68 mmol). Triethylamine (137 mg, 1.35 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 5 h. The solvent was removed by rotary evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1) to give a yellow solid (50 mg, 24% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH3:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:2]1.C([Li])CCC.CCCCCC.O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:48].[Cl-].[Cl-].[Cr+3:51]>O1CCCC1>[Cl-:48].[Cl-:48].[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([Cr+2:51])[CH:2]=1)([CH3:15])[CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: [Cr+3]
Reactant: C=CCCC(C)(C1=CCc2ccccc21)c1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCC(C)(C1=CC([Cr+2])c2ccccc21)c1ccccn1
Temperature: -100 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A solution of 4.81 g (0.01747 mol) of 2-[1-(1H-inden-3-yl)-1-methyl-4-pentenyl]pyridine in 60 ml of tetrahydrofuran was cooled to −100° C. 11.5 ml of a 15% strength n-butyllithium solution in hexane (0.01834 mol) were slowly added dropwise. After the addition was complete, the reaction mixture was stirred at −100° C. for a further 1 hour. The mixture was subsequently allowed to warm to room temperature. After stirring for a further 2 hour, the solution was cooled to −60° C. and 7.07 g (0.0189 mol) of chromium trichloride tris(tetrahydrofuran) were added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred at room temperature for a further 10 hours. The solid which had precipitated was filtered off, washed with diethyl ether and dried under reduced pressure. Recrystallization from a mixture of dichloromethane and diethyle ether gave 2.5 g of (3-(2-pyridyl-1-methyl-4-pentenyl)indenyl)chromium dichloride (36%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]([OH:44])[CH2:41][NH:42][CH3:43])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:42]([CH2:41][CH:40]([OH:44])[C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH3:26])[CH:35]=4)[CH3:43])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1cccc(OCCOCCOC)c1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCCOc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (85 mg, 0.21 mmol), 1-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}-2-(methylamino)ethanol (Preparation 44) (85 mg, 0.32 mmol) and diisopropylethylamine (56 μL, 0.32 mmol) in dry DMF (4.4 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with ice (6 g). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (10 mL, 1:1, v/v, dissolved with warming acetonitrile, diluted with water and then cooled to 0° C. overnight) gave the title compound (107 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2[Cl:36])=[O:22])[CH2:17]1>>[Cl:36][C:27]1[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:26]=1[C:25]([NH:24][CH2:23][C:21](=[O:22])[NH:20][CH:18]1[CH2:19][N:16]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[CH2:3][CH2:4]2)[CH2:17]1)=[O:37]
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1Cl)NC1CNC1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(C(F)(F)F)ccc4Cl)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in Example 13 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-2-chloro-5-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)(=[O:33])[CH3:32]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A172) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (490 mg, 70%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=[C:7]([I:21])[N:6]=1.O>CS(C)=O>[I:21][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(COc2ccc(I)nc2Br)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(COc2ccc(I)nc2OC)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
Sodium methoxide (11 g) was added to a solution of 2-bromo-6-iodo-3-[(4-methoxybenzyl)oxy]pyridine (17 g) in dimethyl sulfoxide (90 mL), and the mixture was stirred at 90° C. for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→70:30) to give 6-iodo-2-methoxy-3-[(4-methoxybenzyl)oxy]pyridine as a colorless powder (10 g, 71%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Li]CCCC.C1COCC1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.Cl>C1COCC1>[O:23]=[C:17]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C1CCC(=O)O1
Reactant: O=C1CCCN1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)N1CCCC1=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of 2-oxopyrrolidine (5.00 g) in THF (60 ml) was cooled to -50° C., and a 1.55 M n-BuLi/THF solution (38 ml) was dropwise added thereto. After 0.5 hour's stirring at -30° C., succinic anhydride (6.00 g) was added dropwise, followed by stirring at a temperature of -30°--20° C. for 0.5 hour. The reaction mixture was poured into ice water and adjusted to pH 4 with 1N hydrochloric acid, and extracted with n-butanol. The organic layer was washed with saturated brine and concentrated to give 9.42 g of 4-oxo-4-(2-oxo-1-pyrrolidinyl)butyric acid.
Reaction SMILES: [SH2:1].[NH2:2][C:3](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C.N1C=CC=CC=1>>[NH2:2]/[C:3](/[C:4]([CH3:7])([CH3:5])[CH3:6])=[C:8](\[C:9]#[N:10])/[C:11](=[S:1])[NH2:12]
Reactant: CC(C)(C)C(N)=C(C#N)C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)/C(N)=C(/C#N)C(N)=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With cooling, 1.52 g (4.50 mmol) of hydrogen sulphide are introduced as a gas into a mixture of 1.6 g (1.40 mmol) of (1-amino-2,2-dimethylpropylidene)propanedinitrile, 1.41 g (1.40 mmol) of triethylamine and 2.21 g (2.80 mmol) of pyridine. For 1 h, nitrogen is then passed through the reaction mixture, and the reaction mixture is then added to ice-water and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure.