Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CCCCCCCCCC.C(OO)(C)(C)C.NC1C=CC=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C.O>[CH3:15][S:12]([N:11]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4][CH:3]1[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:1])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Nc1ccccc1CCC(=O)c1ccccc1
Agent: CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCCCCCCCCC
Solvent: Nc1ccccc1
Solvent: O
Product: CS(=O)(=O)N1c2ccccc2CC1C(=O)c1ccccc1
Reaction time: 14 h
Yield: 85 %

Procedure:
A reactor was charged with 303 mg (1.0 mmol) of N-(2-(3-oxo-3-phenylpropyl)phenyl)methanesulfonamide (an3) obtained in Synthesis Example 7, 36.9 mg (0.10 mmol) of tetrabutylammonium iodide (Bu4N+I−), and 50 mL of ethyl acetate as a solvent to prepare a solution. Subsequently, 364 μL of 5.5 M decane solution (manufactured by Aldrich) containing 2.0 mmol of tert-butyl hydroperoxide (TBHP) as an oxidizing agent was added to the solution in an amount corresponding to 2 equivalents based on the aniline derivative (an3). After adjusting the temperature of the reaction system to room temperature (about 20° C.), the mixture was stirred for 14 hours, and then stirred (reacted) at 50° C. for 4 hours. After cooling the reaction mixture including the reaction product to room temperature, the reaction mixture was added to 20 mL of water, and extracted twice with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium sulfite (Na2SO3) aqueous solution, an NaCl aqueous solution, and water, followed by the addition of anhydrous sodium sulfate (Na2SO4). The solvent was then evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=6/1) to obtain (1-(methylsulfonyl)indolin-2-yl)(phenyl)methanone (white solid) represented by the following formula (as3). The yield was 85% (see Table 1-2). The analysis data for the resulting compound (as3) is shown below.
Reaction SMILES: Cl.N[C@@H](C)CSC1SC2C=CC=CC=2N=1.SC1SC2C=CC=CC=2N=1.C(O[C@@H]1[C@H](OC(=O)C2C=CC=CC=2)[C@@H](COC(=O)C2C=CC=CC=2)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C1C=CC=CC=1.C([O:78][C@@H:79]1[C@H:83]([O:84]C(=O)C2C=CC=CC=2)[C@@H:82]([CH2:93][O:94]C(=O)C2C=CC=CC=2)[O:81][C@H:80]1[N:103]1[C:125]2[N:124]=[C:123]([Cl:126])[N:122]=[C:107]([NH:108][C@@H:109]([CH3:121])[CH2:110][S:111][C:112]3[S:113][C:114]4[CH:120]=[CH:119][CH:118]=[CH:117][C:115]=4[N:116]=3)[C:106]=2[N:105]=[CH:104]1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[Cl:126][C:123]1[N:122]=[C:107]([NH:108][C@@H:109]([CH3:121])[CH2:110][S:111][C:112]2[S:113][C:114]3[CH:120]=[CH:119][CH:118]=[CH:117][C:115]=3[N:116]=2)[C:106]2[N:105]=[CH:104][N:103]([C:125]=2[N:124]=1)[C@@H:80]1[O:81][C@H:82]([CH2:93][OH:94])[C@@H:83]([OH:84])[C@H:79]1[OH:78]
Reactant: C[C@@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[C@H](N)CSc1nc2ccccc2s1
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: C[C@@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 49 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(S)-2-amino-1-propylthio]benzothiazole hydrochloride [prepared by a Mitsunobu reaction as laid out in Example 1 using 2-[(S)-N-tert-butyloxycarbonyl]amino-1-propanol (3.5 g, 20 mmol) and 2-mercaptobenzothiazole (3.35 g, 20 mmol) followed by acidic hydrolysis] (1.1 g, 4.2 mmol) with 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.8 g, 4.5 mmol), followed by debenzoylation of the purified 2',3',5'-tri-O-benzoyl-2-chloro-N-[(S)-1-(2-benzothiazolyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title 2-chloro-N-[(S)-1-(2-benzothiazolyl)thio-2propyl]adenosine (0.88 g, 49%) (following column chromatography), 1H NMR (DMSO-d6) δ 1.38 (3H, d, --CHCH3), 3.50-3.68 (4H, m, H-5'a, and H-5'b and --CH2 --), 3.95 (1H, d, H-4'), 4.12 (1H, d, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.34, 7.45 (2H, 2t, Ar-H), 7.85, 7.98 (2H, 2d, Ar-H), 8.40 (1H, s, H-8), 8.52 (1H, s, N--H). HPLC retention time 20.1 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)Cl>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:11]([C:9]1[S:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(C(=O)O)s1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(=O)NCCN(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To 5-(ethoxycarbonyl)thiophen-2-carboxylic acid (250 mg) is added successively methylene chloride (3.0 mL), N,N-dimethylethylenediamine (100 mg), 1-hydroxybenzotriazole (205 mg), triethylamine (610 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (290 mg). The mixture is stirred at room temperature overnight. The reaction mixture is diluted with chloroform and thereto is added a saturated sodium hydrogencarbonate solution. After stirring, the organic layer is separated and concentrated in vacuo. The residue is purified by flash column chromatography on NH-silica gel (Solvent; ethyl acetate) to give ethyl 5-[[[2-(dimethylamino)ethyl]amino]carbonyl]thiophen-2-carboxylate (160 mg, yield; 53%) as brown crystals. MS (APCI) m/z: 271 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:31][CH:30]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), (4-methoxyphenyl)boronic acid (2.0 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride (30 mL) was added copper(II) acetate (2.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.15 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Br:17])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:19].[Li+]>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:16][C:15]1[C:14]([Br:17])=[CH:13][CH:12]=[CH:11][C:10]=1[C:9]([OH:18])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1c(Br)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a stirred solution of 4-bromo-1-oxo-1,3-dihydro-isoindole-2-carboxylic acid tert butyl ester (0.206 g, 0.66 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of aq. lithium hydroxide (1M, 2 ml, 1.98 mmol) and the mixture stirred at room temperature under nitrogen for 18 hours. The mixture was diluted with diethyl ether (30 ml) and washed with 1M HCl (10 ml). The aqueous layer was extracted with diethyl ether (2×20 ml) and the combined organics dried over magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure to give the title compound (0.188 g, 86%) as a white waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[F:42][C:39]([F:40])([F:41])[CH2:38][NH:37][C:36](=[O:43])[O:35][CH2:34][C@@H:31]1[CH2:32][O:33][C@H:28]([CH2:27][CH2:26][C:25]2[C:24]([NH:23][C:10](=[O:11])[CH2:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=3)=[CH:54][CH:53]=[CH:52][C:51]=2[F:55])[CH2:29][NH:30]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: O=C(O)C[C@@H](c1ccc(F)cc1)c1cncc(C(F)(F)F)c1
Product: O=C(C[C@@H](c1ccc(F)cc1)c1cncc(C(F)(F)F)c1)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 8 and 9 of Example 89. MS (ES) m/z=675 (M+H)+.
Reaction SMILES: [C:1]1([CH3:46])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:13][CH:12]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([O:42]CC)=[O:41])[CH:35]=3)=[O:32])[C:11]2=[O:45])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:46])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[O:23])[CH2:13][CH:12]([NH:30][C:31](=[O:32])[NH:33][C:34]3[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=3)[C:40]([OH:42])=[O:41])[C:11]2=[O:45])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C3CCCCC3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)C1CCCCC1
Yield: 50.3 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (168 mg) solution (12 ml) and tetrahydrofuran (12 ml) were added, and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride (50ml). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and isoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 240 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([C:20]([C:22]3[N:26]4[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:30][C:25]4=[N:24][C:23]=3[O:35][CH3:36])=[O:21])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].[BH4-].[Li+].O>C(O)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH:20]([OH:21])[C:22]3[N:26]4[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:30][C:25]4=[N:24][C:23]=3[O:35][CH3:36])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14]
Reactant: COc1nc2cc(C(F)(F)F)ccn2c1C(=O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1nc2cc(C(F)(F)F)ccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
[step 5] (E)-2-{3-fluoro-8-[2-methoxy-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carbonyl)dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.100 g, 0.197 mmol) obtained in step 4 was dissolved in ethanol (0.985 mL) and THF (0.985 mL), lithium borohydride (0.44 g, 1.2 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was discontinued with water, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (E)-2-(3-fluoro-8-{hydroxy[2-methoxy-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (100 mg, 100%).
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[CH3:13][C:14]1([CH3:26])[CH2:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([SH:25])[CH2:16][CH2:15]1>C(O)(=O)C>[CH3:26][C:14]1([CH3:13])[CH2:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([S:25]([OH:3])(=[O:2])=[O:1])[CH2:16][CH2:15]1
Reactant: CCOC(=O)C1=C(S)CCC(C)(C)C1
Reactant: O
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCC(C)(C)C1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 107.2 %

Procedure:
Sodium peroxyborate tetrahydrate (46.3 g) was admixed with acetic acid (270 ml) and heated to 50 to 55° C. and then a solution of ethyl 5,5-dimethyl-2-mercapto-1-cyclohexene-1-carboxylate (20.2 g) synthesized in Reference Example 17 in acetic acid (30 ml) was, added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 8 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (450 ml) and stirred at room temperature for 4 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (120 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (330 ml) and stirred at room temperature for 15 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (300 ml) and the powder which precipitated was isolated by a filtration to yield ethyl 5,5-dimethyl-2-sulfo-1-cyclohexene-1-carboxylate as an orange oil (26.5 g) containing inorganic substances. This (26.3 g) was dissolved in thionyl chloride (79 ml) and then stirred at 80 to 90° C. for 7.5 hours. The solution was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (150 ml). The solution thus obtained was combined with dilute brine (200 ml) and partitioned, and then the ethyl acetate layer was washed twice with saturated brine (100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/8) to yield ethyl 2-chlorosulfonyl-5, 5-dimethyl-1-cyclohexene-1-carboxylate (12.4 g) as a brown oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[N:21]\[S:18]([N:13]2[C:14]3([CH2:16][CH2:15]3)[CH2:17][N:10]([C:4]3[C:5]4[CH:9]=[CH:8][NH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH2:11][CH2:12]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: COc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N\S(=O)(=O)N2CCN(c3ncnc4[nH]ccc34)CC23CC3)cc1

Procedure:
7-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaza-spiro[2.5]octane-4-sulfonic acid amide (intermediate 1) (0.46 mmol) was suspended en dry toluene (5 ml), added 4-methoxybenzaldehyde (0.46 mmol) and stirred at reflux for 48 h. The obtained reaction mixture was concentrated in vacuo on silica. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: OCc1ccnc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Clc1cc(COC2CCCCO2)ccn1
Yield: 78.3 %

Procedure:
To a mixture of (2-chloropyridin-4-yl)methanol (7.0 g, 48.8 mmol) and 3,4-dihydro-2H-pyran (20.5 g, 244 mmol) in THF (80 mL), 4-methylbenzenesulfonic acid (840 mg, 4.88 mmol) was added. The reaction mixture was stirred at reflux overnight, and the solvent was removed under reduced pressure. The residue was diluted with H2O (200 mL), and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to afford 2-chloro-4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine as a yellow oil (8.7 g, 78%). MS (ES+) C11H14ClNO2 requires: 227, found: 228[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:28]([F:31])([F:30])[F:29])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[C:16]([CH:22]=2)[C:17]([O:19]CC)=[O:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1>Cl>[Cl:8][C:6]1[CH:5]=[C:4]([CH:9]([C:28]([F:29])([F:31])[F:30])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[C:16]([CH:22]=2)[C:17]([OH:19])=[O:18])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Agent: Cl
Product: O=C(O)c1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of (E)-ethyl 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100° C. for 18 h. The reaction was cooled to ambient temperature, resulting in a white solid precipitate. The precipitate was filtered to afford the title compound as a white solid (0.12 g, 60%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.O.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>>[CH2:10]1[CH2:11][CH:9]1[NH2:12].[Br:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Agent: NC1CC1
Solvent: O
Product: Brc1cscn1
Temperature: 50 °C

Procedure:
Commercially available 2,4-dibromothiazole (2 mmol) is dissolved in cyclopropylamine (3 mL) and the reaction mixture is heated to 50° C. for 8 hour. The cooled mixture is then poured into water and extracted 2 times with ether. After drying the combined organic fractions (MgSO4), evaporation of solvents, and purification by flash column chromatography (silica gel, 15% EtOAc/Hexane) furnished 2-cyclopropylamine-4-bromothiazole which is further converted to the corresponding stannane 186f. A solution of 2-cyclopropylamine-4-bromothiazole in degassed DME is treated with hexamethylditin and Pd(PPh3)4 and heated at 80° C. for 18 hour. The cooled mixture is concentrated under vacuum and the residue is purified by column chromatography eluting with 20% EtOAc/Hexane/2% Et3N to give Stannane 186f. [M+H]+=304.1.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH2:10][CH2:9][CH:8]=2)=[N:4][C:3]=1[C:12]([NH:14][C:15]1[CH:16]=[N:17][N:18]([CH3:29])[C:19]=1[C@@H:20]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[C@H:23]([F:28])[CH2:22][O:21]1)=[O:13]>CO.[Pd]>[NH2:1][C:2]1[S:6][C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:12]([NH:14][C:15]1[CH:16]=[N:17][N:18]([CH3:29])[C:19]=1[C@@H:20]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[C@H:23]([F:28])[CH2:22][O:21]1)=[O:13]
Reactant: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(C3CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-N-(5-((2S,5R,6S)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(cyclopent-1-en-1-yl)thiazole-4-carboxamide (Example 333) in methanol was added 10% palladium on carbon, and the mixture was stirred under an atmosphere of hydrogen overnight. After filtration and in vacuo concentration, purification by HPLC provided the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.79 (s, 1H), 7.05 (s, 2H), 4.83-4.74 (m, 1H), 4.48-4.30 (m, 1H), 4.26-4.12 (m, 1H), 4.11-3.91 (m, 1H), 3.74 (s, 3H), 2.07-1.97 (m, 3H), 1.88-1.52 (m, 11H). LCMS (ES+) m/z 423 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.O>[CH3:11][C:12]1([CH2:18][CH:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1(CCO)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1(CC=O)CCCCC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
Step D To a solution of oxalyl chloride (2.18 g, 17.2 mmol) (Aldrich) in dichloromethane (12 mL) at −78° C. was added the solution of dimethyl sulfoxide (2.44 mL, 34.3 mmol) in dichloromethane (8 mL) dropwise. After 5 mins, the solution of 2-(1-methyl-cyclohexyl)-ethanol (2.2 g, 15.6 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (7.8 mL, 56 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give (1-methyl-cyclohexyl)-acetaldehyde as a light yellow oil (Yield: 2 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:8].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>[OH-].[Na+]>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][O:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:8]
Reactant: O=c1[nH]ccc2c(O)cccc12
Reactant: OCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]ccc2c(OCC(O)CO)cccc12
Yield: 85.6 %

Procedure:
16 g of 5-hydroxyisocarbostyril was dissolved in 110 ml of a 1N aqueous sodium hydroxide solution, and 8 g of glycidol was added to the solution. The mixture was then refluxed for 2 hours while stirring. After allowing the mixture to cool, the precipitated crystals were filtered, and recrystallized from water to give 20 g of 5-(2,3-dihydroxy)propoxyisocarbostyril as colorless needle-like crystals having a melting point of 228° - 230° C.