Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:17]([OH:22])[OH:18])=[C:3]([CH3:11])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(C)c(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(B(O)O)c(C)c1
Temperature: -78 °C
Yield: 82.8 %

Procedure:
An oven-dried three-neck round-bottom flask equipped with two rubber septum-sealed addition funnels and a sidearm stopcock was evacuated and backfilled with N2. Dry THF (100 mL) and 2-bromo-5-methoxy-1,3-dimethyl-benzene (21.5 g, 0.100 mol) were then added via syringe. The mixture was then cooled to −78° C. with stirring in a dry ice-acetone bath. Next, n-butyl lithium (2.5 M solution in hexane, 44 mL, 0.11 mol) was added dropwise via syringe with stirring over the course of 45 min at −78° C., and the mixture was allowed to stir at −78° C. for an additional 30 min. Triisopropyl borate (28.2 g, 0.150 mol) was then added dropwise via syringe over the course of 30 min at −78° C. After stirring at −78° C. for an additional 1 h, the mixture was quenched with saturated aqueous NH4Cl solution (100 mL), and the resulting mixture allowed to gradually warm to room temperature. The organic layer was next separated, and the aqueous layer was extracted with a mixture of ethyl acetate and THF (1:1, 50 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting sticky oil was suspended in hexane (100 mL) and stirred at room temperature for 30 min. The resulting solid was collected by filtration and washed with hexane to yield 14.9 g of the title compound as a colorless solid (83%). 1H NMR (400 MHz, CDCl3): δ 6.552 (s, 2H), 4.684 (s, 2H), 3.780 (s, 3H), 2.370 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 141.714, 122.607, 112.325, 111.815, 55.238, 22.663. MS (EI): m/z 180.1 [M+, 100]. Anal. Calcd. For C9H13BO3: C, 60.05; H, 7.28. Found: C, 60.27; H, 7.42.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>C1COCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(-c2cnc(I)cn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc(C#C[Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2.30 g (7.37 mmol) 2-iodo-5-(4-methoxyphenyl)pyrazine and 1.56 mL (11.1 mmol) ethynyltrimethylsilane in 30 mL THF is charged with 0.12 g (0.15 mmol) bis(triphenylphosphine)dichloropalladium, 0.03 g (15.0 mmol) CuI and 3.01 mL (22.1 mmol) TEA. After stirring at r.t. for 4 h the reaction mixture is diluted with DCM and washed with 50 mL aq. 5% ammonia solution (1×) and 50 mL water (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is treated with PE/EtOAc (8/2), filtered through a plug of silica gel and the solvent is again removed in vacuo. The product is used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[P:12]12(SP3(SP(SP(S3)(S1)=S)(=S)[S:14]2)=S)=[S:13]>CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([P:12](=[S:14])=[S:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCOc1ccccc1
Solvent: CCCCCC
Product: CCCCOc1ccc(P(=S)=S)cc1
Reaction time: 48 h

Procedure:
n-Butyloxybenzene (Ic) and P4S10 (in a molar ratio of 10:1) were stirred for six hours at 150° C. under anhydrous conditions. The mixture was cooled, hexane was added, and the reaction flask was left for two days at 5° C. The resulting precipitate was recovered by filtration, washed with anhydrous hexane and dried. The yield of product was 37% of theory; after recrystallization from chloroform/petroleum ether it melted at 142°-4° C. Its solubility in tetrahydrofuran was found to be 5 gms/100 ml at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13]
Reactant: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Br
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Cl)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (224 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (201 mg, 0.52 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (295 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL, 2.63 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (hexanes/EtOAc) affording the title compound (153 mg, 43%): LC-MS (ES) m/z=651 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C@H:9]([C:22](O)=[O:23])[C:10]([S:13][C:14](=[S:21])[NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH:9]2[C:10]([CH3:12])([CH3:11])[S:13][C:14](=[S:21])[N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:22]2=[O:23])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCNC(=S)SC(C)(C)[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN(C)CCN1C(=O)C(NC(=O)c2ccc(Cl)cc2)C(C)(C)SC1=S

Procedure:
A mixture of 10 g of N-(p-chlorobenzoyl)-S-(2-dimethylaminoethylthiocarbamoyl)-penicillamine, 2 g of glacial acetic acid and 100 ml of chloroform is stirred under reflux for 5 hours. The solvent is then removed under reduced pressure, and the crude product is recrystallized from a mixture of ethyl acetate and isopropyl ether to give 5-(p-chlorobenzamido)-3-(2-dimethylaminoethyl)-6,6-dimethyl-2-thioxo-tetrahydro-2H-1,3-thiazin-4-one as pale yellow crystals, melting at 152°-153° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1)[C:9](=O)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[NH:14][C:13]=1[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[NH:14][C:13]=1[C:24]1[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2C(=O)C(=O)N(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a solution of N-benzyl-2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]-N-[4-(4-methanesulfonylaminophenyl)butyl]-2-oxo-acetamide (391 mg in 20 mL dry tetrahydrofuran) was added 5.5 mL of a 1M solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (1.8 mL) and heated to reflux on an oil bath. After 3 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (317 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23]CCC(OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[S:13][N:12]=1.CC([O-])(C)C.[K+].Br[CH2:46][CH2:47][O:48][CH3:49].CN(C=O)C>C1COCC1>[CH3:49][O:48][CH2:47][CH2:46][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
To a solution of (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-3-ylthio)propanoate (0.420 g, 0.749 mmol) in THF (10 mL) was added potassium 2-methylpropan-2-olate (2.36 ml, 2.36 mmol) and the reaction was stirred at ambient temperature for 5 minutes. 1-Bromo-2-methoxyethane (0.132 g, 0.899 mmol) (as a solution in 2 mL THF) and DMF (1 mL) were added and the reaction was stirred for 20 minutes at ambient temperature. The solution was quenched with water, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)—N-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.200 g, 50.1% yield).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH3:2].[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:10][C:4]1[CH:5]=[C:6]([CH:8]=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccc(C=O)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1sc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 5-ethyl-2-thiophenecarboxaldehyde (6.0 g) in N,N-dimethylformamide (60 ml) was added N-chlorosuccinimide (8.57 g), and the mixture was stirred at room temperature for 2 hours, and subsequently stirred under heating at 60° C. for 2 hours. N-chlorosuccinimide (4.00 g) was further added thereto, and the mixture was further stirred under heating at 60° C. for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=33:1) to give 4-chloro-5-ethyl-2-thiophenecarboxaldehyde (3.1 g) as colorless oil. (2) The above 4-chloro-5-ethyl-2-thiophenecarboxaldehyde was treated in a manner similar to Reference Example 1 to give 3-bromo-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene as yellow oil. APCI-Mass m/Z 347/349 (M+H+MeOH).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1.I[CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:29][CH:30]=1
Reactant: O=C(CCCI)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)cc1
Yield: 80.6 %

Procedure:
tert-Butyl 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.274 g, 0.672 mmol), 4-iodobutyrophenone (0.18 g, 0.672 mmol), and potassium carbonate (0.14 g, 1.01 mmol) in N,N-dimethylformamide (5 mL) were heated at 65° C. for 3 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.30 g, 80%); MS for C34H39N3O4 m/z 554 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH2:18][C:19]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2]2([CH3:12])[CH3:1])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccc(C(=O)CCl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
10.8 g (66.4 mmoles) 3,3-dimethyl-3H-indol-2-one are slowly added (in 1 h) to a suspension of 26 7 g (200 mmoles) aluminium chloride and 15 g, that is 10.58 ml (133 mmoles) chloroacetyl chloride in 60 ml dichloromethane, then the mixture is heated under reflux for 1 h 30 min. The brown suspension obtained is slowly poured into 500 ml ice-water, the mixture is stirred for 30 min and then filtered and the solid is washed with a little ether and dried. 16.3 g of crystals are obtained, which are used as such in the following step.
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.C[O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([Cl:17])=[CH:13][N:12]=1)=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]([NH2:2])=[O:8])=[N:12][CH:13]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
Suspend ammonium chloride (0.465 g, 8.69 mmol) in toluene (14 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (4.3 mL, 8.69 mmol). After the gas stops evolving, add 5-chloropyrazine-2-carboxylic acid methyl ester (0.500 g, 2.89 mmol). Heat at 50° C. overnight. Cool the reaction mixture to room temperature, then slowly pour into a slurry of silica gel (10 g) in CHCl3 (50 mL). Stir for 10 minutes before filtering. Wash the silica plug with methanol (2× 100 mL) before concentrating. Take the resulting solid up in dichloromethane and wash with water (30 mL) and brine (40 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 50% ethyl acetate in hexanes to give the title compound (0.155 g, 34.0%): TOF MS EI+ 157.0 (M+), HRMS calcd for C5H4N3OCl 157.0043 (M+H)+, found 157.0047, time 4.19 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min. 5-95% over 19 min], tR=7.1 min, 100% purity.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1.[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([CH3:31])=[N:25]2)[CH:21]=[CH:20][C:19]=1[OH:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:8]1[C:3]([CH2:2][O:32][C:19]2[CH:20]=[CH:21][C:22]([N:24]3[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([CH3:31])=[N:25]3)=[CH:23][C:18]=2[CH3:17])=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nnn(-c2cccc(Br)c2CBr)c1=O
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(Br)cccc1-n1nnn(C)c1=O
Yield: 86.7 %

Procedure:
A mixture of 1-(2-bromomethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 11) 3.1 g, 2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol (described in Reference Preparation example 20) 1.6 g, potassium carbonate 1.3 g and acetonitrile 70 ml was stirred with heating under reflux for six hours, and the reaction mixture was then filtered and was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{ 3-bromo-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one 3.1 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH:3]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[O:8])[CH2:2]1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:1]1[CH2:6][CH2:5][S:4][CH:3]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[O:8])[CH2:2]1
Reactant: O=Cc1ccccc1F
Reactant: COC(=O)c1n[nH]c2ccc(NC(=O)C3CNCCS3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1n[nH]c2ccc(NC(=O)C3CN(Cc4ccccc4F)CCS3)cc12
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
In a flask, dichloromethane (5 mL) and acetic acid (3 drops) was added to methyl 5-(thiomorpholine-2-carboxamido)-1H-indazole-3-carboxylate (0.320 g, 1 mmol) and 2-fluorobenzaldehyde (0.248 g, 2 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (0.636 g, 3 mmol) was added in one portion. The reaction was stirred for an additional 16 hours. Saturated sodium bicarbarbonate (20 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (30×1 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by flash column chromatography to give 250 mg product. LC-MS: 429.1.2 [M+H].
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:11]1[C:16](O)=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1>>[CH3:2][C:1]([N:5]1[CH2:8][CH:7]([CH2:9][O:10][C:16]2[CH:15]=[CH:14][C:13]([CH3:18])=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)N1CC(CO)C1
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(OCC2CN(C(C)(C)C)C2)cc1

Procedure:
Following the procedures of Example 8, the title compound is prepared from 1-t-butyl-3-azetidinemethanol and p-cresol.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O1CCOCC1>O>[C:1]([N:5]([CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCC(C)(C)CCN(C(=O)C(=O)OCC)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C#CCC(C)(C)CCN(C(=O)C(=O)O)C(C)(C)C
Temperature: 50 °C
Yield: 106.6 %

Procedure:
A mixture of 250 mg of 24d, 250 mg of KOH, 3 ml of dioxane and 1 ml of water was heated at oil bath at 50° C. for 1 hr. The mixture was poured onto water and extracted once with heptane/ether 1/1. The aqueous phase was acidified with cold 1N HCl to pH3 and extracted with ethyl acetate. The organic extract was once washed with sat. NaCl and dried and concentrated, to give 240 mg of 24e, as colorless oil. NMR (CDCl3) δ 1.00 (s, 6, 2×CH3), 1.50 (s, 9, tertC4H9), 2.00 (t, 1, acetylene), 1.70 (m, 2, CH2), 2.10 (m, 2, CH2), 3.71 (m, 2, CH2).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1>CN(C)C=O>[C:1]([O:9][CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COC(=O)c2ccccc2)O1
Temperature: 150 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
Sodium benzoate (40.64 g, 0.282 mol) was added to a mixture of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (42.38 g, 0.282 mol) prepared by the same manner as example 3 and N,N-dimethylformamide (400 ml) and the resulting mixture was stirred for 3 days at 150° C. After cooling the salt was filtered off and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo to give 58.63 g of crude (R)-4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2OC)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
To a mixture of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]acetaldehyde (D103) (87.6 mg, 0.217 mmol) and ethyl 4-piperidinecarboxylate (137 mg, 0.870 mmol) in Dichloromethane (DCM) (5 mL) was added 3 drops of HOAc. The mixture was stirred at room temperature for 20 min. Then sodium triacetoxyborohydride (92 mg, 0.435 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight (16 h). The reaction was quenched with water. DCM was removed. The residue was extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to afford ethyl 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylate (D104) (38.7 mg). MS (ES): C28H34ClN3O4S requires 513.2. found 514.2 (M+H+).