Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21](Cl)(=[O:23])=[O:22].[CH3:25][NH:26][CH3:27]>C(Cl)Cl.O>[CH3:25][N:26]([CH3:27])[S:21]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:6]=1)(=[O:23])=[O:22]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)Cl)c3cc(F)ccc32)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)N(C)C)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
A solution of 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)indole (2.52 g) in DCM (75 mL) is added to an aqueous solution of dimethylamine (40%, 20 mL) in water (50 mL) and stirred at rt for 20 h. The organic phase is separated, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-1-(toluene-4-sulfonyl)-1H-indole-3-sulphonic acid dimethylamide (2.55 g, 99%) as a solid. MS: 397 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.C[O-].[Na+].[Cl-].[NH4+:24]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]([NH2:24])=[NH:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: N#Cc1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N=C(N)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
With heating, 0.7 g (2.8 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbonitril was dissolved in 150 ml of abs. methanol, and 1 ml of a solution of sodium methoxide in methanol (30%, corresponds to 5.4 mmol) was added. The mixture was stirred at 65° C. until the thin-layer chromatogram (TLC) showed complete conversion, 1.5 g of ammonium chloride was added and the mixture was concentrated. The residue was boiled twice with in each case 30 ml of ethanol, the hot mixture was filtered and the combined filtrates were concentrated slightly. The mixture was allowed to stand at RT for 20 min, and the precipitate formed was filtered off with suction, washed with MTBE and dried on a rotary evaporator.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:8]([O:12][C:13]([NH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:21][CH:22]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.2 g (10 mmol) of isopropylsulphonic acid chloride are added dropwise to a solution of 1.0 g (4.8 mmol) of 4-tert.butoxycarbonylamino-aniline in 10 ml of pyridine. The mixture is stirred for 18 hours at ambient temperature. Then the reaction solution is poured onto 150 ml of ice water and then extracted with ethyl acetate. The organic phases are washed with water and freed from solvent. The residue is chromatographed on silica gel (dichloromethane/methanol/NH4OH=19:1:0.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[CH3:23][N:24]([CH3:31])[CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH2:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][N:24]([CH3:31])[CH3:23])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN(C)CC(C)(C)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(C)(C)CNC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and N,N,2,2-tetramethyl-1,3-propanediamine (3.652 mL, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was washed with brine, 2N NaOH (aq.), dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeOH/DCM) gave the title compound as a yellow oil 17171/2/1 (2.29 g, 77%).
Reaction SMILES: C(=O)([O-])[O-].[K+:5].[K+].[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:30][CH2:29][CH:28]([O:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:27][CH2:26]3)[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:12]=[CH:13][CH:14]=1)#[N:8]>O.CO>[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:26][CH2:27][CH:28]([O:31][CH2:32][C:33]([O-:35])=[O:34])[CH2:29][CH2:30]3)[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:12]=[CH:13][CH:14]=1)#[N:8].[K+:5]
Reactant: N#Cc1cccc(-c2nc(C3CCC(OCC(=O)O)CC3)cc3cccnc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(-c2nc(C3CCC(OCC(=O)[O-])CC3)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (10.1 mg, 0.074 mmol) in water (1 ml) is added to a solution of {4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]cyclohexyloxy}-acetic acid (59 mg, 0.15 mmol) in methanol (6 ml). The reaction mixture is stirred at room temperature for 30 minutes, filtered and concentrated. The product is lyophilised from water (×3) then dried at 40° C. in vacuo for 18 hours. Recrystallisation from CH2Cl2/ether gives the product. m.p 148-150° C. (decomp.) MS (ES+) [M+H]+ 388.1635
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Cl[C:17]1[C:18]([O:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)[CH2:26][CH2:25]2)=[N:19][CH:20]=[CH:21][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[O:1]1[CH2:6][CH:5]=[C:4]([C:17]2[C:18]([O:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([NH:30][C:31]4[S:32][C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[N:35]=4)[CH2:28][CH2:29]3)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Clc1nccnc1O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C1=C(c2nccnc2O[C@H]2CC[C@H](Nc3nc4ccccc4s3)CC2)CCOC1
Temperature: 80 °C

Procedure:
A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.10 g, 0.49 mmol) and N-(trans-4-(3-chloropyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.14 g, 0.39 mmol), prepared as in step 1 of example 9a, in 1,2-dimethoxyethane (2 mL) and aqueous sodium carbonate (2 M, 0.58 mL, 1.16 mmol) was placed under nitrogen atmosphere using 3 evacuation/backfill cycles. Tetrakis triphenylphosphine(palladium) (0.022 g, 0.019 mmol) was added and one more evacuation/backfill cycle was executed. The mixture was then heated to 80° C. After 4 h the mixture was cooled to RT and partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.13 g, 0.32 mmol, 83% yield). [M+1] 409.2. IC50 (uM): 0.03702.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH3:30][C:31]1[S:35][C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])=[N:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[S:35][C:31]([CH3:30])=[CH:32][N:33]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ncc(C)s5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Reaction time: 12 h

Procedure:
The title compound is prepared analogously as described for example 1 (however, stirring is performed for 12 h at RT) using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(5-methyl-1,3-thiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B37), HBTU (167 mg), DIPEA (207 mg) and DCM (10 ml). The crude product is purified by flash column chromatography for three times [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] to yield the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:7][CH:6]=[C:5]([C:8](OC)=[O:9])[CH:4]=1.CO.[BH4-].[Na+]>C1COCC1>[F:12][C:2]([F:1])([F:13])[C:3]1[S:7][CH:6]=[C:5]([CH2:8][OH:9])[CH:4]=1
Reactant: COC(=O)c1csc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of methyl 5-(trifluoromethyl)thiophene-3-carboxylate (523 mg) in THF (1 ml)-MeOH (1 ml) was added NaBH4 (2.2 g) at room temperature, and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was quenched with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (449 mg) as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:27]N1C(=O)CCC1=O>ClCCl.CN(C)C=O>[Br:27][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[NH:1][CH:2]=1
Reactant: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 339B (1 g) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was cooled in an ice bath. N-bromosuccinimide (0.582 g) was added and the mixture was stirred overnight while warming to ambient temperature. The reaction was concentrated and the crude product was chromatographed on silica gel with a methanol/methylene chloride gradient.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][S:6][CH:5]1[C:12]1[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=1[OH:22])(=[O:3])[CH3:2].[C:23](OC1NCC(OC(=O)C)S1)(=O)C>>[CH3:23][O:10][C:9]([CH:8]1[CH2:7][S:6][CH:5]([C:12]2[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=2[OH:22])[N:4]1[C:1](=[O:3])[CH3:2])=[O:11]
Reactant: CC(=O)Oc1ccc(O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Reactant: CC(=O)OC1CNC(OC(C)=O)S1
Product: COC(=O)C1CSC(c2cc(OC(C)=O)ccc2O)N1C(C)=O

Procedure:
The procedure described above for preparation of 3-acetyl-2-(2-hydroxy-5-acetyloxyphenyl)-1,3-thiazolidine-4-carboxylic acid (4) was followed to prepare 9, except that a 2,5-diacetyloxy thiazolidine starting material was employed.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[Br:17]Br>CCO>[Br:17][CH2:16][C:2](=[O:1])[CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(CCC(C)=O)cc1
Reactant: BrBr
Solvent: CCO
Product: CCOC(=O)c1ccc(CCC(=O)CBr)cc1
Temperature: 25 °C

Procedure:
21-1 (3.13 g, 14.2 mmol) was dissolved in EtOH (30 mL) at 0°, and Br2 (805 μL, 15.6 mmol) was added. After warming to RT for 16 h the reaction was concentrated, diluted with Et2O, washed with water and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% EtOAc/hexane) provided 21-2 as a white solid.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([N:23]([CH3:29])[C@H:24]([C:26]([OH:28])=O)[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].Cl.C[O:32][C:33](=[O:44])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[NH2:35]>C(OCC)(=O)C>[N:23]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])([CH3:29])[C@H:24]([C:26]([NH:35][C@H:34]([C:33]([OH:44])=[O:32])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)=[O:28])[CH3:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
1 liter of ethyl acetate under nitrogen is cooled to between -5° and 0° C. and isobutyl chloroformate (37.6 ml, 290 mmole) is added followed by N-methylmorpholine (31.9 ml, 290 mmole). A sticky white solid forms and after 10 minutes BOC-N-methylalanine (58.9 grams, 290 mmoles) is added. A more granular solid forms and after 20 minutes tyrosine methylesterhydrochloride (57.93 grams, 250 mmoles) is added. Additional N-methylmorpholine (27.9 ml, 250 mmoles) is then added to obtain a pH of about 8. After 2.5 hours of stirring the mixture is washed three times with 500 ml of 1 N sodium bicarbonate and three times with 500 ml of 0.5 molar citric acid and dried over sodium sulfate. The reaction mixture is concentrated in vacuo affording the following crops of crystalline materials:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2([CH2:23][CH2:22][C:21](=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]2)[S:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([O:18][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:17])[C:10]2([CH2:19][CH2:20][C:21](=[CH:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:23]2)[S:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OCc1ccccc1
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 25.1 %

Procedure:
In 10 ml of methylene chloride was dissolved 0.56 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. At ambient temperature, 0.21 g of benzyl alcohol, 0.23 g of 1-hydroxybenzotriazole monohydrate and 0.31 g of dicyclohexyl carbodiimide were successively added. After stirring the resulting mixture for 24 hours at the same temperature as above, the insoluble matter was filtered off. The filtrate was washed successively with 2 mol/L hydrochloric acid, water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=6:1] gave 0.17 g of benzyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate as a light yellow oily product.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])[CH2:16]1
Reactant: CCNC(=O)C1CCCC(c2ccc(OCOC)cc2OCOC)C1
Solvent: CO
Product: CCNC(=O)C1CCCC(c2ccc(O)cc2O)C1
Yield: 10.7 %

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-N-ethylcyclohexanecarboxamide (25 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated to reflux for 4 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a solid (2 mg, 12%). δH(CD3OD) 1.80 (3H, t), 1.30-1.60 (4H, m), 1.74-1.94 (4H, m), 2.26-2.36 (1H, m), 2.82-2.92 (1H, m), 3.16 (2H, q), 6.21-6.26 (2H, m), 6.88 (1H, d); m/z (ES+) 264 (M+H)+.
Reaction SMILES: C([C:3]([C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH:5]=[CH:6][N:7](C)[CH3:8])#N.S(=O)(=O)(O)[OH:22]>>[CH3:20][O:19][C:17](=[O:18])[C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:5][CH:6]=[N:7][C:8]=1[OH:22]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)C(C#N)=C(C=CN(C)C)c1ccc(C)cc1
Product: COC(=O)c1c(-c2ccc(C)cc2)ccnc1O
Temperature: 0 °C
Yield: 60.9 %

Procedure:
117.0 g (0.54 mol) of 1-cyano-1-methoxycarbonyl-4-(N,N-dimethylamino)-2-(4-methylphenyl)-1,3-butadiene was added to 250 ml of concentrated sulfuric acid at a temperature below 20° C. under stirring, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 l of ice water, and the precipitated material was filtrated out. The filtrate was adjusted to pH 6 with sodium hydroxide aqueous solution to precipitate the aimed product, which was then filtrated out. The material thus precipitated was washed with water and methanol, and was dried to obtain 74.9 g of a white crystal of the aimed product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](S(C)(=O)=O)=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[F:33][C:34]([F:50])([F:49])C1C=C(C=CC=1)CC(C(O)=O)C(O)=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:34]([F:50])([F:49])[F:33])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)nc12
Reactant: O=C(O)C(Cc1cccc(C(F)(F)F)c1)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3cccc(C(F)(F)F)c3)c(Cl)nc12
Temperature: 105 °C

Procedure:
A heterogeneous mixture of (4-amino-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.3 g, 6.04 mmol, Intermediate 13: step c), 2-(3-(trifluoromethyl)benzyl)malonic acid (2.06 g, 7.85 mmol, Intermediate 15: step b) and POCl3 (10 mL) was heated at 105° C. for 4 hours. The mixture was cooled to room temperature and concentrated to remove excess POCl3. Ice water was then added and the mixture treated with aqueous NH4OH (kept adding ice during addition) to a basic pH 8-9. The aqueous mixture was extracted with EtOAc (2×). The EtOAc extracts were dried over Na2SO4, evaporated in vacuo and chromatographed (DCM/EtOAc, gradient) to provide the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]2[N:15]=[C:16]([NH2:18])[N:17]=[C:13]2[CH:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=1>>[CH:1]1([NH:7][C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Reactant: NC1CCCCC1
Product: Nc1nc2cc(-c3cccnc3)cc(NC3CCCCC3)n2n1

Procedure:
A mixture of cyclohexylamine (4 mL) and 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A, (280 mg, 1.14 mmol) was microwaved at 155° C. for 1 h. On cooling, the product was triturated with toluene/cyclohexane, then taken up in CH2Cl2 and washed with aqueous Na2CO3. The organic layer was separated, dried (MgSO4), then concentrated to provide N5-cyclohexyl-7-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine. MS m/z 309 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][NH:5]2
Reactant: Cc1ccc2nccnc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)NCCN2
Temperature: 0 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
To a solution of 6-methylquinoxaline (2 g, 13.87 mmol) and nickel (II) chloride hexahydrate (6.6 g, 27.74 mmol) in anhydrous methanol (70 mL) was added in portions, sodium borohydride (10.5 g, 277.43 mmol) while maintaining the temperature between 0° C. and 5° C. The reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 4 hours. Removal of the solvent under reduced pressure was ensued by acidification of the residue with 2N HCl (600 mL). The mixture was stirred at room temperature for 16 hours and filtered. The green filtrate was made basic (pH 10-11) using concentrated NH4OH (150 mL) and extracted with diethylether (3×200 mL). The ethereal extracts were successively washed with water (2×300 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave 6-methyl-1,2,3,4-tetrahydroquinoxaline as a solid (880 mg, 43%).
Reaction SMILES: [CH:1]([PH2:5])([CH2:3][CH3:4])[CH3:2].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH:1]([P:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)P
Reactant: C=CCCCCCC
Product: CCCCCCCCP(CCCCCCCC)C(C)CC
Temperature: 80 °C

Procedure:
75 g (0.8 mol) sec.-butyl phosphine, 900 ml (5.2 mol) octene-1 and 1.8 g (11 millimol) ABIN were placed in a 2-liter flask with stirrer, reflux condenser and dropping funnel, and heated to 80° C. Next, a solution of 6.2 g ABIN in 400 ml octene was added dropwise within 3 hours. The temperature was maintained at 80°-85° C. over a period of 8 hours, and the reaction product was ultimately distilled under reduced pressure. Low boiling matter was removed and 190 g of a liquid colorless product was obtained.