Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:6][CH:7]=1>CS(C)=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[S:6][CH:7]=[C:3]([CH:2]=[O:1])[N:4]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2nc(CO)cs2)cc(OC)c1OC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nc(C=O)cs2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
4-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)thiazole (1.53 g) was dissolved in a mixed solvent of DMSO (5 mL) and triethylamine (2.3 mL), and sulfur trioxide pyridine complex (98%, 3.09 g) was added portionwise to the solution at room temperature. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:2) to obtain the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1)=[O:3])[CH3:6]
Reactant: On1nnc2ccc(Cl)cc21
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)On1nnc2ccc(Cl)cc21
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A solution of ethyl chloroformate (2.17 g.) in benzene (10 ml.) was dropwise added to a solution of 1-hydroxy-6-chloro-1H-benzotriazole (3.38 g.) and triethylamine (2.80 ml.) in benzene (30 ml.) under ice-cooling and stirring. Benzene (30 ml.) was further added to the mixture and the reaction temperature was slowly elevated to room temperature, and the mixture was allowed to stand overnight. Precipitated crystals were filtered off and the filtrate was concentrated. Benzene was added to the residue and an insoluble material was filtered off, after which the filtrate was concentrated to give 1-ethoxycarbonyloxy-6-chloro-1H-benzotriazole (2.2 g.), crystal. These crystals, the precipitated crystals filtered off and the insoluble material in benzene were put together, in turn washed with water, a sodium bicarbonate aqueous solution, 1N hydrochloric acid and water, and recrystallized from methanol (75 ml.) to give the object compound (3.5 g.), white needles, mp 160° to 162° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH:22]([NH2:30])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13](=[O:15])[NH:30][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Product: Cc1ccc(C(NC(=O)CNC(=O)CCc2ccccc2)c2ccccc2)cc1

Procedure:
Prepared in analogy to example 1.1 from (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and rac-C-phenyl-C-p-tolyl-methylamine (CA [55095-21-1]).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:28][CH:27]=1
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 49.9 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (320 mg, 1.03 mmol) was reacted with 4-[(dimethylamino)methyl]aniline (210 mg, 1.54 mmol) to afford the desired product (218 mg, 50%) as a yellow solid: ESI MS m/z 425 [C22H22BrN3O+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:15]1(/[CH:20]=[N:21]/[S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl.C1COCC1>[CH:15]1([C@@H:20]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)[S@@](=O)/N=C/C1CCCC1
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)S(=O)N[C@H](c1ccccn1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A solution of 2-bromopyridine (11.8 mL, 19.5 g, 123.5 mmolin dry THF (50 mL) was added carefully to i-PrMgCl.LiCl (1.3 M in THF, 95.0 mL, 123.5 mmol). The resulting solution was stirred at rt for 3 h after which it was added dropwise, over 45 min, to a −48° C. solution of (R,E)-N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (19.1 g, 95.0 mmol) in dry CH2Cl2 (250 mL). The resulting mixture was stirred at −48° C. for 1 h before being allowed to slowly warm up to rt over 16 h. The reaction was quenched by addition of saturated aq NH4Cl (200 mL). H2O (200 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine (150 mL). The organic layer was dried (Na2SO4) and was concentrated under reduced pressure yielding the crude product (28.6 g, 5:1 d.r. (RS,S)—(RS,R)) as a clear red oil. The crude product was purified by repeated flash chromatography on silica gel using 1:19 MeOH-EtOAc as eluent in combination with trituration of the obtained solids with cyclohexane which eventually gave the pure product (8.80 g, 33%) as a white solid; 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (d, J=4.5 Hz, 1H), 7.63 (dt, J=1.0, 7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.16 (dd, J=4.5, 7.5 Hz, 1H), 4.26 (dd, J=5.0, 8.5 Hz, 1H), 3.95 (d, J=5.0 Hz, 1H), 2.44-2.31 (m, 1H), 1.94-1.83 (m, 1H), 1.68-1.44 (m, 5H), 1.44-1.32 (m, 1H), 1.30-1.17 (m, 1H), 1.13 (s, 9H).
Reaction SMILES: CN(C=O)C.S(Cl)(Cl)=O.[NH:10]1[C:14]([C:15]([OH:17])=O)=[N:13][N:12]=[N:11]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[C:28]([NH2:30])[N:29]=2)=[CH:21][CH:20]=1.Cl>C(#N)C.N1C=CC=CC=1.O.C1C=CC=CC=1>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[S:26][CH:27]=[C:28]([NH:30][C:15]([C:14]3[NH:13][N:12]=[N:11][N:10]=3)=[O:17])[N:29]=2)=[CH:23][CH:24]=1
Reactant: O=C(O)c1nnn[nH]1
Reactant: Cc1ccc(-c2nc(N)cs2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CC#N
Product: Cc1ccc(-c2nc(NC(=O)c3nnn[nH]3)cs2)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture, obtained by adding ice-cooled dry DMF(0.53 ml, 6.48 mmol) and then thionyl chloride (0.499 ml, 6.84 mmol) to dry benzene (1.5 ml,, was allowed to warm up to room temperature and to react for 10 minutes upon which the mixture separated into two layers. The lower layer was added dropwise to dipotassium salt of 1H-tetrazole-5-carboxylic acid (867 mg, 4.56 mmol) suspended in dry acetonitrile (15 ml) under ice-cooling. The mixture was allowed to react for 15 minutes. After adding dropwise a mixed solution of 2-(4-methylphenyl)-4-thiazolamine (928 mg, 4.88 mmol) in dry acetonitrile (15 ml) and dry pyridine (4 ml) under the same conditions, the mixture was allowed to warm up to room temperature and to react for 1 hour. After dissolution was effected with addition of water, the reaction mixture was acidified under ice-cooling with 2N-HCl to pH 2. The deposited solids were filtered with suction, washed with water and recrystallized from methanol-water to give yellowish crystals (677 mg. yield 52%) of N-(2-(4-methylphenyl)-4-thiazolyl)-1H-tetrazole-5-carboxamide (Ia-5), m.p.228°-230° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:28][N:27]=4)[CH:21]=3)[N:13]=2)[CH:9]=[N:8]1)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:28][N:27]=4)[CH:21]=3)[N:13]=2)[CH:9]=[N:8]1
Reactant: CC(=O)OCCn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)n2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1ccc(-c2cnn(CCO)c2)nn1Cc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
918 mg (1.65 mmol) of 2-[4-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)pyrazol-1-yl]ethyl acetate are dissolved in 5 ml of methanol, 73 mg (1.81 mmol) of sodium hydroxide are added, and the mixture is stirred at room temperature for 15 h. A precipitate forms in the process, which is filtered off with suction and triturated with methanol.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([CH2:25][C:26]1([C:31](=[O:47])[NH:32][CH:33]([C:43](=[O:46])[NH:44][CH3:45])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])(C)(C)C>FC(F)(F)C(O)=O>[O:19]=[C:18]1[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11](=[O:24])[N:10]1[CH2:9][CH2:8][CH:7]([CH2:25][C:26]1([C:31](=[O:47])[NH:32][CH:33]([C:43](=[O:46])[NH:44][CH3:45])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:6]([OH:48])=[O:5]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)O)CCCC1

Procedure:
A solution of 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]cyclopentylmethyl}butyric acid tert-butyl ester (diastereomer A) (45 mg, 0.069 mmol) in trifluoracetic acid (1 mL) was stirred overnight at room temperature. The solvent was evaporated under vacuum leaving a white foam which was triturated with ether to afford 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]-cyclopentylmethyl}butyric acid (diastereomer A) as a white solid, 33 mg (80%). High Resolution Mass Spectrum M+ calculated for C34H37N3O7 : 599.2632; found:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][C@H:32]2[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]2)=[O:17])=[N:14][CH:15]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](O)CC2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (114 mg, 0.271 mmol) obtained in Example 12 in methylene chloride (3 ml), trans-4-aminocyclohexanol hydrochloride (49 mg, 0.325 mmol), 1-hydroxybenzotriazole (37 mg, 0.271 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg, 0.325 mmol) and 4-methylmorpholine (71 μl, 0.650 mmol) were added, and the mixture was stirred for 17 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:40) was concentrated under reduced pressure, to obtain the title compound (129 mg, 0.249 mmol, 92%) as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[C:13]([CH2:15][CH3:16])[S:14][C:8]=2[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)=[CH:20][CH:19]=2)[C:6]1=[O:36].Cl.[NH2:41][O:42][CH3:43].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C.C(O)C>[CH2:15]([C:13]1[S:14][C:8]2[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][C:33](=[O:35])[O:32][N:31]=4)=[CH:20][CH:19]=3)[C:6](=[O:36])[N:5]([CH2:4][C:3](=[N:41][O:42][CH3:43])[C:2]([CH3:38])([CH3:1])[CH3:39])[C:10](=[O:11])[C:9]=2[CH:12]=1)[CH3:16]
Reactant: CON
Reactant: CCc1cc2c(=O)n(CC(=O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=NOC)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
A mixture of 3-(3,3-dimethyl-2-oxobutyl)-6-ethyl-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.20 g), (aminooxy)methane hydrochloride (0.15 g), pyridine (2 mL) and ethanol (2 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.077 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10](Cl)=[O:11])[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:11])[CH2:6]1
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2Cl)C1
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CCNC(=O)N1CCC(Oc2cccc(Cl)c2Cl)C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution 11.8 g (0.04 mole) of 3-(2,3-dichlorophenoxy)-1-pyrrolidinecarbonyl chloride in 50 ml of chloroform was stirred at 5° C. in an ice bath while the following were added in order: 25 g of ice, 5.52 g of potassium carbonate and 3.87 g (0.044 mole) of N,N-dimethylethylenediamine. The resulting mixture was stirred for 20 hours and worked up by adding additional water followed by separation of the organic phase. The chloroform solution was dried over magnesium sulfate, filtered and concentrated in vacuo to a dark amber oil, 14 g, which solidified on standing. TLC analysis (10% methanol/chloroform) showed 3 spots; therefore, the crude product was chromatographed on 50 g of Fluorisil. Elution with chloroform gave a dark forerun which was discarded, the main portion was collected and rechromatographed through a 50 g Florisil column. The column was washed with 200 ml of methanol and the 2 fractions (chloroform and methanol) were combined before concentrating on a rotary evaporator to give a light amber oil which solidified. Recrystallization from isopropyl ether gave a beige crystalline product; 4.5 g (34%), m.p. 94°-95° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[CH2:3][CH2:2]1.Cl>[OH-].[Na+].CO.O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCOCC1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
Methyl tetrahydro-2-H-pyran-4-carboxylate (400 μL, 3.00 mmol) was dissolved in a 5:1 mixture of 10M NaOH and MeOH (4.0 ml: 0.8 ml). The mixture was heated to 60° C. for 3 hours. After the reaction was complete, all volatiles were removed under high vacuum to leave a residual solid. The residue was dissolved in H2O and subsequently acidified to pH˜1 using aqueous HCl. The acidic aqueous phase was extracted with DCM and dried over Na2SO4. The solvent was removed to give tetrahydro-pyran-4-carboxylic acid (339 mg, 87%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[ClH:18]>CO>[ClH:18].[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1,1-dimethylethyl 4-(methylsulfonyl)-1-piperazinecarboxylate (360 g, 1.36 mol) in MeOH (1 L) was added HCl (6 M in MeOH, 2 L) dropwise. The mixture was stirred at rt for 1 h. About 1 L of MeOH was rotovapped off. The resultant precipitate was filtered, washed with MeOH, and dried on high vacuum to provide the title compound of Step B (A combination of 2 batches, 570 g) which was used without further purification. 1H NMR (400 MHz, D2O) δ 2.95 (s, 3H), 3.27-3.29 (m, 4H), 3.42-3.46 (m, 4H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([C:59]1[S:60][C:61]([CH2:64]O)=[CH:62][N:63]=1)[CH2:57][CH3:58]>C1COCC1>[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:64][C:61]3[S:60][C:59]([CH2:56][CH2:57][CH3:58])=[N:63][CH:62]=3)=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCc1ncc(CO)s1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCc3cnc(CCC)s3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 2-propylthiazol-5-yl-methanol (prepared by LiAlH4 reduction of methyl 2-propylthiazole-5-carboxylate). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].C(N(CC)CC)C.Cl>C(N(CC)CC)C.C(O)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2=O
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ncc2c1CCC[C@@H]2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirred solution of (4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (16.7 g, 75.0 mmol) in formic acid-triethylamine azeotropes (molar fraction of triethylamine: 0.2857, 45 mL) was added chloro-[(1S,2S)-N-(p-tolunenesulfonyl)-1,2-diphenylethanediamine](mesitylene)ruthenium(II) (1.86 g, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and then at 45° C. for 2.5 hours with occasional venting. After cooling to room temperature, 1N hydrochloric acid (50 mL) was added, followed by extraction with ethyl acetate (200 mL×3). The organic layers were combined, washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (gradient elution, 0-4% methanol in dichloromethane) to afford ((S)-4-hydroxy-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (14.3 g, 85%) as a white solid with enantiomerical purity ≧99% as determined by Chiralpak™ IA column (condition: gradient: 50% hexane in ethanol, flow rate: 15 mL/min and retention time: 5.8 min for A enantiomer and 8.1 min for B enantiomer).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:25][CH:26]=[CH:27][C:28]([F:31])([F:30])[F:29])(=O)=O>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]([CH2:25][CH:26]=[CH:27][C:28]([F:31])([F:30])[F:29])[C:14]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC=CC(F)(F)F
Reactant: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Product: Cc1c(C)n(CC=CC(F)(F)F)c2c(OCc3ccccc3)nncc12
Yield: 20.7 %

Procedure:
The title compound was prepared as pale yellow crystals in 20.7% yield in a similar procedure to that described in Example 41-by using 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine and 4,4,4-trifluoro-2-butenyl methanesulfonate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[N:15]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[C@H:25]2[CH2:30][C@@H:29]([NH:31]C(=O)OC(C)(C)C)[C@@H:28]([S:39][CH3:40])[C@@H:27]([CH3:41])[CH2:26]2)=[O:17])[CH:13]=[CH:12][C:11]=1[F:42]>O1CCOCC1>[NH2:31][C@H:29]1[C@@H:28]([S:39][CH3:40])[C@@H:27]([CH3:41])[CH2:26][C@@H:25]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:18][C:16](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([F:42])=[C:10]([C:4]3[C:3]([F:2])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])[N:15]=2)[CH2:30]1
Reactant: CS[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CS[C@@H]1[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of HCl (30.0 equiv.) in dioxane was added to tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylthio)cyclohexylcarbamate (1.0 equiv.). The solution was capped and left standing at rt for 1 hr. The volatiles were removed in vacuo, dissolved in DMSO and purified by reverse phase HPLC to yield N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylthio)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 94% yield. LC/MS (m/z)=487.2 (MH+), Rt=0.65 min. 1H NMR (400 MHz, <dmso>) δ ppm 10.44 (s, 1H), 8.58 (d, J=4.0, 1H), 8.47 (d, J=4.0, 1H), 8.34 (dd, J=8.0, 4.0, 1H), 8.20 (dd, J=8.0, 8.0, 1H), 8.20 (dd, J=16.0, 4.0, 1H), 7.67-7.74 (m, 1H), 7.36 (dd, J=8.0, 8.0, 2H), 7.26 (d, J=4.0, 1H), 2.85-2.95 (m, 2H), 2.18 (s, 3H), 1.88-1.98 (m, 1H), 1.74-1.84 (m, 1H), 1.48-1.56 (m, 1H), 1.38-1.48 (m, 1H), 1.18-1.28 (m, 1H), 1.02 (d, J=8.0, 3H).
Reaction SMILES: [CH:1]1([CH2:8][NH:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1N(CC2CCCC2)C(=O)N(CC2CCCC2)[C:24](=[O:41])[CH:23]=1>>[NH2:21][C:22]1[N:9]([CH2:8][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:10](=[O:11])[N:12]([CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:24](=[O:41])[CH:23]=1
Reactant: O=C(NCC1CCCCCC1)NCC1CCCCCC1
Reactant: Nc1cc(=O)n(CC2CCCC2)c(=O)n1CC1CCCC1
Product: Nc1cc(=O)n(CC2CCCCCC2)c(=O)n1CC1CCCCCC1

Procedure:
In the manner of step (b) of Example 1, 1,3-bis(cycloheptylmethyl)urea (from step (a), 3.99 g, 14.23 mmol) was converted to 6-amino-1,3-bis(cyclopentylmethyl)uracil (3.22 g, 65%), m.p. 194°-197° C.; 1H-NMR (DMSO-d6) consistent with structure.