Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C@H]1C(O)=O)(=[O:13])=[O:12].COC1C=CC(C[N:49]2[N:53]=[N:52][C:51]([CH2:54][N-:55][CH3:56])=[N:50]2)=CC=1.C([SiH](CC)CC)C.[C:66](O)([C:68](F)(F)F)=[O:67]>>[CH3:56][N:55]([CH2:54][C:51]1[NH:52][N:53]=[N:49][N:50]=1)[C:66]([C@@H:68]1[CH2:16][C@@H:17]([SH:19])[CH2:18][N:14]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:12])=[O:13])=[O:67]
Reactant: C[N-]Cc1nnn(Cc2ccc(OC)cc2)n1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CC[SiH](CC)CC
Product: CN(Cc1nnn[nH]1)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 57 %

Procedure:
A solution of 150 mg (0.19 mmol) of a 1:1 mixture of (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid [1-(4-methoxy-benzyl)-1H- and [2-(4-methoxy-benzyl)-2H-tetrazol-5-ylmethyl]-methyl-amide in 10 ml TFA was treated with 0.3 ml (1.9 mmol) triethylsilane, refluxed for 7 min at 80° C. and evaporated. Crystallization from CH2Cl2/Et2O gave 46 mg (57%) (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl-(1H-tetrazol-5-ylmethyl)-amide, mp: 175 slow dec., MS: 433 (MH+).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:12][C:13]#[N:14]>CN(C)C=O>[C:2]1([S:8]([CH2:12][C:13]#[N:14])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: N#CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCS(=O)(=O)c1ccccc1
Temperature: 40 °C

Procedure:
Benzene sulfinic acid sodium salt, 49.2 g. (0.3 mole) was combined with 400 ml. of dimethyl formamide in a 1 liter flask. The mixture was stirred at 40°C. Chloroacetonitrile, 22.5 g. (0.3 mole) was added over a period of 5 minutes. The resulting mixture was stirred and heated at 40°-45°C. for 2 hours. The reaction mass was then poured into 600 ml. of water, and the solid insoluble product was collected by suction filtration and dried. There was obtained a yield of 29.8 g. of the title compound, m.p. 111°-112°C.
Reaction SMILES: O[C@@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:26]=[C:25]([O:27][CH2:28][C:29]2[CH:30]=[N:31][S:32][CH:33]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].[O:34]1CCCC1>>[C:21]([C:20]1[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[N:31][S:32][CH:33]=2)=[CH:26][C:19]=1[O:34][CH:4]([CH2:3][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:5]([OH:7])=[O:6])#[N:22]
Reactant: N#Cc1ccc(OCc2cnsc2)cc1F
Reactant: Cc1ccccc1[C@H](O)CCC(=O)[O-]
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1CCC(Oc1cc(OCc2cnsc2)ccc1C#N)C(=O)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium (R)-4-Hydroxy-4-(2-methylphenyl)butanoate (0.39 g) is added in one portion to a stirred suspension of sodium hydride (0.11 g, 60% dispersion in mineral oil) in tetrahydrofuran (30 mL) and the mixture is stirred at 50° C. for 1 hour. A solution of 2-fluoro-4-(isothiazol-4-ylmethoxy)benzonitrile (0.21 g) in tetrahydrofuran (20 mL) is added and the reaction mixture is stirred at reflux for 16 hours. The reaction mixture is concentrated in vacuo and water is added to the residue. The solution is acidified with 1 N hydrochloric acid and extracted with ethyl acetate (50 mL). The organic phase is washed with water (50 mL), with brine (50 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give (R)-4-[(2-cyano-5-(isothiazol-4-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, (0.02 g) in the form of a yellow oil. [NMR (CDCl3) (300 MHz): -2.2-2.4 (m, 2H), 2.45 (s, 3H), 2.6-2.65 (m), 2.75-2.8 (m,1H), 5.0 (q, 2H), 5.5 (dd,1H), 6.15 (d,1H), 6.5 (dd, 1H), 7.2 (m, 3H), 7.4 (m,1H), 7.45 (d,1H), 8.45 (d, 2H)].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2c2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cn1c(=O)c2c(nc(C3CCN(C(=O)OCc4ccccc4)CC3)n2Cc2ccccc2)c2ccccc21
Yield: 83.2 %

Procedure:
As described in example 3 step E, 4-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (50 mg, 0.102 mmol), was alkylated by treating with NaH (5 mg, 0.12 mmol, 60% in mineral oil), and benzyl bromide (26 mg, 0.15 mmol) to give after work-up and chromatography, 4-(3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (43 mg, 83% yield). 1H-NMR (CDCl3): δ 8.34 (dd, 1H, J=8.0, 1.6 Hz), 7.53 (m, 1H), 7.42 (m, 1H), 7.26-7.37 (m, 9H), 7.10 (m, 2H), 5.91 (m, 2H), 5.13 (s, 2H), 4.28 (m, 2H), 3.79 (s, 3H), 2.89 (m, 3H), 1.98 (m, 2H), 1.68 (m, 2H). MS: calculated for C24H24N4O3+H 507.2; found: 507.6.
Reaction SMILES: C1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([Cl:9])[Cl:8])C=CC=CC=1.[Cl:16][SiH](Cl)Cl>[Cl-].[Al+3].[Cl-].[Cl-]>[C:10]1([Si:7]([Cl:8])([Cl:9])[Cl:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)c1ccccc1
Yield: 114 %

Procedure:
380 g of diphenyldichlorosilane, 22.5 g of anhydrous aluminium chloride and 0.2 g of hydrated alumina (water content : 27%; specific surface area : 5.8 m2 /g) are introduced into a flask. 478 g of trichlorosilane are run in over the course of 7 hours, whilst keeping the reaction mixture at 70°C and distilling the dichlorosilane. A fraction weighing 77 g, containing 74% of dichlorosilane, is obtained. 362 g of phenyltrichlorosilane are obtained on distilling the mixture remaining in the flask.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH2:13]Cl)=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[P:16]([O:21]C)([O:19][CH3:20])[O:17][CH3:18]>CCCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([CH2:13][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(OC)OC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Solvent: CCCCCCC
Product: COP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OC

Procedure:
To 16.1 grams of 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol dissolved in 40 ml. of dry n-heptane was added 9.55 grams of trimethyl phosphite. One-third of the trimethyl phosphite was initially added dropwise at room temperature, the remainder being added dropwise at 70°. The reaction mixture was then heated at reflux (97°) for ten hours and the residual white solid isolated by stripping off the volatiles by distillation at 50° to 60° at reduced pressure. The residue was triturated twice with petroleum ether and recrystallized, after clarification, from a solvent mixture of n-hexane and isopropanol yielding the desired product as white crystals melting at 146° to 148°. (compound 1)
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6].Cl.[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.O>[CH2:8]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6])=[O:30])=[CH:32][CH:33]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: OCC=CCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC=CCO)cc1
Reaction time: 4 h

Procedure:
To a mixture of 8.8 g. of 1,4-dihydroxy-2-butene and 2.84 g. of 4-dimethylaminopyridine is added 4.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. The heat evolution is moderated with ice and stirring is continued for 4 hours. Chloroform and water are added and the chloroform extract chromatographed to remove any diacylated by-product. Evaporation to crystallization yields the 4-hydroxy-2-buten-1-yl 4-(n-hexadecylamino)benzoate as a white solid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C.Cl>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([B:29]([OH:30])[OH:28])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a stirred suspension of 4-(4-n-pentoxyphenyl)bromobenzene (1.0 g, 3.13 mmol) in anhydrous tetrahydrofuran (20 ml) at -78° C. under a nitrogen atmosphere was added n-butyllithium in hexanes (2.5M, 1.32 ml, 3.30 mmol). After a period of 15 min, triisopropylborate (760 μl, 3.30 mmol) was added. Stirring at -78° C. was continued for 15 min and then at 25° C. for 40 min. The mixture was acidified with 0.5N HCl (20 mL) and then partitioned between ether (50 ml) and water (40 ml). The organic phase was washed with water (3×) and brine and dried with magnesium sulfate. The solvent was removed in vacuo to give 4-(4-n-pentoxyphenyl)phenylboronic acid (750 mg) as a white solid: 1H NMR (400 MHZ, DMSO-d6) δ 0.89 (t, 3, J=7.2 Hz), 1.38 (m, 4 ), 1.72 (m, 2), 3.99 (t, 2, J=6.5 Hz), 6.99 (d, 2, J=8.8 Hz), 7.57 (d, 2, J=8.2 Hz), 7.60 (d, 2, J=8.8 Hz), 7.83 (d, 2, J=8.2 Hz).
Reaction SMILES: [CH:1]([C:3]1[S:7]/[C:6](=[N:8]\[CH3:9])/[N:5]([CH3:10])[C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.C(O)(=O)C>[CH3:10][N:5]1[C:4]([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)=[C:3]([CH2:1][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[S:7]/[C:6]/1=[N:8]\[CH3:9]
Reactant: C1COCCN1
Reactant: C/N=c1\sc(C=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C/N=c1\sc(CN2CCOCC2)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C

Procedure:
tert-Butyl 4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate (1.0 g) obtained in Example 35a) and morpholine (0.36 mL) were dissolved in a mixed solution of 1,2-dichloroethane (50 mL) and acetic acid (0.18 mL). Triacetoxy sodium borohydride (0.84 g) was added thereto at 0° C., and the mixture was mixed at room temperature overnight. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.2 g) as pale brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([C:24]2([OH:27])[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:23]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1c(Cl)cccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Yield: 58.8 %

Procedure:
To a solution of 1-bromo-3-chloro-2-fluorobenzene (5.0 g, 23.8 mmol) in dry tetrahydrofuran (50 mL) under nitrogen at −78° C., was added dropwise n-butyllithium (2.5 M in tetrahydrofuran, 9.5 mL, 23.8 mmol). The mixture was stirred for 0.5 h at −78° C. after which a solution of 1-N-boc-3-pyrrolidinone (4.37 g, 23.8 mmol) in dry tetrahydrofuran (20 mL) was added drop wise. The resulting mixture was brought to ambient temperature, aqueous saturated ammonium chloride (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 4:1 to 1:1) gave the title compound (4.42 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 1), 259 (16), 214 (31), 157 (17), 57 (bp).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]=O>>[CH2:25]([O:24][C:23]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:17][C:16]=1[CH3:15])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(C)c2)c(O)c([N+](=O)[O-])c1
Yield: 66.2 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (345 mg, 1.76 mmol) and 3-methyl-4-benzyloxybenzaldehyde (400 mg, 1.76 mmol) were reacted according to the same procedure as Preparation 22 to give 470 mg (Yield 66%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29](O)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH3:34])[C:29](=[O:30])[CH2:28][C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CNC
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and dimethylamine.
Reaction SMILES: Cl[S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:4])=[O:3].[CH2:18]([OH:20])[CH3:19].C(N(CC)CC)C.O>C(OCC)C>[CH2:18]([O:20][S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:3])=[O:4])[CH3:19]
Reactant: CCO
Reactant: O=C(O)C(c1ccc2c(c1)CCO2)S(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOS(=O)(=O)C(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
α-Chlorosulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid (5 mmole) is added to 30 ml of ethyl ether. To this mixture is added 5 mmole of ethanol in 10 ml of ethyl ether which contains 10 mmole of triethylamine. The mixture is stirred at 20° C. for about 1 hour and 50 ml of water is added. The pH is adjusted to about 6.5 and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated to give α-ethoxysulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@@:18]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[C@H:20]([CH3:21])[O:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@:18]([OH:19])([C@H:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1)[CH3:21])[CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](N1NCc2ccccc21)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a suspension of indazole (0.059 g, 0.5 mmol), 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (0.105 g, 0.416 mmol) in N,N′-dimethylformamide (2.5 ml) was added anhydrous potassium carbonate (0.069 g, 0.5 mmol), followed by radiating microwaves thereon with stirring at 180° C. for 5 min. Thereafter, the addition of water (0.5 ml) at 0° C. terminated the reaction. The reaction solution was diluted with ethyl acetate (10 ml) and washed with saturated ammonium chloride solution (10 ml) and then with brine (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The crude product was purified by chromatography on silica gel to give the title compound (Yield 44%).
Reaction SMILES: C1C=CC=CC=1.[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=[O:13].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:8]1[S:7][CH:11]=[CH:10][N:9]=1
Reactant: O=Cc1nccs1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: c1csc(C2OCCO2)n1
Temperature: 25 °C

Procedure:
A benzene (10 mL) solution of 2-thiazole carboxaldehyde (5.00 g 44.19 mmol), ethylene glycol (7.40 mL, 132.58 mmol) and p-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) was refluxed with azeotropic removal of H2O for 3 h and then cooled to ambient temperature. The reaction mixture was diluted with Et2O and the organics washed with sat'd NaHCO3, brine and then dried (MgSO4), filtered and concentrated to provide the title compound as a reddish oil. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=3.1 Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 6.13 (s, 1H), 4.16–4.01 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:18]=[CH:17][NH:16][N:15]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[NH3:5].[CH2:25]([N:5]1[CH2:4][CH2:3][C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:18]=[CH:17][NH:16][N:15]=3)[CH:9]=2)[CH2:7][CH2:6]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC1(c2cccc(-c3nc[nH]n3)c2)CCNCC1
Reactant: CCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(C)(c2cccc(-c3nc[nH]n3)c2)CC1
Product: N
Yield: 18.6 %

Procedure:
To a solution of 4-methyl-4-(3-(1H-1,2,4-triazol-3-yl)phenyl)piperidine (Preparation 45, 55 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydrogencarbonate (28 mg, 0.34 mmol) and bromohexane (32 μL, 0.23 mmol). The resultant mixture was heated at 50° C. for 2 h and then allowed to cool. The mixture was partitioned between water (5 mL) and dichloromethane (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (20 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with methanol:dichloromethane:0.88 ammonia (10:90:1) to give the title compound as a clear oil (7 mg, 9%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)[nH]n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)[nH]n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a solution of N-tert-butyl-2-(3-methyl-1H-pyrazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 56.4 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (129 mg, 86.8 μL, 1.13 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1 mL), methanol (0.5 mL) and ammonium hydroxide (0.15 mL) and stirred at room temperature for 1 h. Purification by chromatography (silica, 20-50% [10% methanol/dichloromethane/0.5% ammonium hydroxide]/dichloromethane) gave N-tert-butyl-2-(3-methyl-1H-pyrazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 31.9 μmol, 57%) as a light brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.19 (s, 1H), 10.12 (s, 1H), 9.53 (s, 1H), 8.07 (s, 1H), 7.93 (d, J=3.0, 1 H), 7.81 (s, 1H), 6.33 (s, 1H), 2.19 (s, 3H), 1.45 (s, 9H); MS (EI/CI) m/z: 314.1 [M+H].
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([O:12]C1CCCCO1)[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].O1CCCC1CC(O)=O.O>>[Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C)(C)C(/C=C/Br)OC1CCCCO1
Agent: O=C(O)CC1CCCO1
Solvent: O
Product: CCCCC(C)(C)C(O)/C=C/Br

Procedure:
A mixture of 3.19 g. (10 moles) of 1-bromo-4,4-dimethyl-3-tetrahydropyranyloxy-trans-1-octene (Example 1173) and 90 ml. of 3:1:1 tetrahydrofuran-acetic acid-water is stirred at ambient temperatures for 20 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel. The title compound is isolated using 10-20% ethyl acetate in benzene.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])(=O)[CH3:2].[CH2:15]([O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([NH2:25])=[C:20]([CH3:26])[CH:19]=1)[CH3:16].[NH2:27][NH2:28]>>[CH2:15]([O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([N:25]2[C:1]([CH3:2])=[C:4]3[C:5]([C:9]([CH3:10])=[N:27][N:28]=[C:12]3[CH3:13])=[C:6]2[CH3:7])=[C:20]([CH3:26])[CH:19]=1)[CH3:16]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: NN
Reactant: CCOc1cc(C)c(N)c(C)c1
Product: CCOc1cc(C)c(-n2c(C)c3c(C)nnc(C)c3c2C)c(C)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (308 mg, 1.56 mol), 4-ethoxy-2,6-dimethyl-phenylamine (250 mg, 1.0 mmol) and hydrazine (100 μL) reacted to give 6-(4-ethoxy-2,6-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]-pyridazine as yellow solid: 1H NM (CDCl3, 500 MHz) δ 6.81 (s, 1H), 6.75 (s, 1H), 4.04 (q, 2H), 2.82 (s, 6H), 2.44 (s, 6H), 2.47 (s, 3H), 2.35 (s, 6H), 1.79 (s, 3H), 1.88 (t, 3H), ; MS (ESI) 324 (M+H)+.