Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[P:14](Cl)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15].[NH4+].[Cl-].Cl>CCOCC>[CH2:17]([O:16][P:14]([O:3]/[C:4](/[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:5]\[C:6]([O:8][CH3:9])=[O:7])([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: CCOP(=O)(Cl)OCC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCCC/C(=C/C(=O)OC)OP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To NaH (60% in mineral oil, 2.8 g, 70 mmol) suspension in ether at 0° C. was added methyl 3-oxoheptanoate (10 g, 63 mmol) in anhydrous ether (50 mL) dropwise under Ar. The reaction mixture was stirred for 30 minutes. Diethyl chlorophosphate (9.6 mL, 67 mmol) was added dropwise under Ar at 0° C. The reaction mixture was stirred overnight allowing warm to room temperature. Saturated aqueous NH4Cl (22 mL) was added to quench the reaction. The mixture was then acidified with 1.0 N HCl. After separation, organic phase was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, concentrated. After column purification (silica gel, 1:1 EtOAc/Hexanes), the product was obtained as a colorless oil (17 g, 91%). 1HNMR (CDCl3) δ 0.89˜0.93 (m, 3H), 1.30˜1.45 (m, 3M), 1.50˜1.60 (m, 2H), 2.42 (m, 2H), 3.68 (s, 3H), 4.20˜4.35 (m, 4H), 5.35 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1)[CH3:22]>C(#N)C>[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4])[CH3:22]
Reactant: CN(C)CC1CCCCN1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Solvent: CC#N
Product: CN(C)CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[(dimethylamino)methyl]piperidine to give colorless crystals, Mp. 208°-209° C. (acetonitrile/activated charcoal).
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([OH:18])=O)([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[SH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1.N1C=CC=CC=1>ClCCl>[CH3:12][C:2]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([S:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[O:18])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CCCCCCCCCC(C)(C)c1cc(C(=O)O)ccc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(C)(C)c1cc(C(=O)Sc2ccc(C(=O)O)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Crude 3-(1,1-dimethyldecyl)-4-methoxybenzoic acid, prepared starting with 1.6 g (5 mmoles) of 3-(1,1-dimethyldecyl)-4-methoxybenzoic acid, described in Example 11 of European Patent No. 0.232.199 is dissolved in 20 ml of dichloromethane. The solution is slowly added to a mixture of 771 mg (5 mmoles) of 4-mercaptobenzoic acid and 8 ml of pyridine. The reaction mixture is stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in water, acidified to pH 5 with 1N HCl and extracted o with ethyl ether (500 ml). The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is purified by chromatography on a silica column, by using as the eluant ethyl ether. 1.92 g (84% yield) of 4-[3-(1,1-dimethyldecyl)-4-methoxybenzoylthio] benzoic acid whose melting point is 186°-187° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reaction time: 3 h
Yield: 287.3 %

Procedure:
(4-Hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (480 mg, 0.71 mmol) was dissolved in DCM (3 mL) and cooled to −78° C. (dry ice/acetone). Dess-Martin periodinane (331 mg, 0.78 mmol) was added to the reaction which was allowed to warm to r.t and stir for 3 h. A 1:1 solution of saturated sodium bicarbonate and sodium sulfite (20 mL) was added and the reaction mixture stirred vigorously for 15 min. The organic layer was isolated, washed with saturated sodium bicarbonate (10 mL), dried (Na2SO4) and evaporated to dryness to afford the desired compound (480 mg, 100%). m/z 258 [M++Na]+
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[Br:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br>O1CCCC1.O>[Br:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:9]1[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: BrCCCCCCBr
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1-c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(CCCCCCBr)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 385.5 %

Procedure:
Part A. To a solution of 4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazole (2.5 g, 0. 00734 mol) (B. Lipshutz, B. Huff, W. Hazen, Tetrahedron Letters, 29, 3411-14, 1988), in dry tetrahydrofuran (50 mL) cooled to -78° under a nitrogen atmosphere, n-butyl lithium in hexane (2.5M, 0.00734 mol) was added slowly. The reaction mixture was stirred for 1 hour and 1,6-dibromohexane (2.68 g, 0.0011 mol) was added rapidly, stirred for 1/2 hour and was allowed to warm to ambient temperature and stirred for 2 additional hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a viscous oil. The product was purified by flash chromatography on silica gel (250 mL) eluting with hexane:ethyl acetate (70:30 v:v) to give 6-bromo-1-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]imidazol-2-yl)hexane as an oil (2.18 g, 0.00424 mol). 1H NMR (CDCl3) δ 7.53-7.16(m,10H), 5.10(s,2H), 3.48(t,2H), 3.34(t,2H), 2.90(t,2H), 1.99-1.5 (m,8H), 0.875(t,2H), 0.008(s,9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Cl[C:18]1[CH:19]=[CH:20][N:21]2[C:26]([CH:27]=1)=[C:25]([CH2:28][CH3:29])[C:24]1[S:30][NH:31][C:32](=[O:33])[C:23]=1[C:22]2=[O:34]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH:19]=[CH:20][N:21]3[C:26]([CH:27]=2)=[C:25]([CH2:28][CH3:29])[C:24]2[S:30][NH:31][C:32](=[O:33])[C:23]=2[C:22]3=[O:34])=[CH:5][CH:4]=1
Reactant: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(Cl)cc12
Reactant: NCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(-c3ccc(CN)cc3)cc12

Procedure:
Under an atmosphere of argon, tetrakis(triphenylphosphine)palladium(0) (20.4 mg, 0.018 mmol), 4-aminomethylphenylboronic acid (110.0 mg, 0.587 mmol), and a 1 M aqueous solution of sodium bicarbonate (1.75 mL, 1.75 mmol) were added sequentially to a solution containing 7-chloro-9-ethyl-1-thia-2,4a-diazacyclopenta[b]naphthalene-3,4-dione (33.0 mg, 0.118 mmol) and dimethylformamide (3.0 mL). The resulting orange mixture was irradiated in a microwave for 15 min (110° C.; 300 W) to give a red mixture. The solvent is evaporated under reduced pressure (˜10 mm Hg, 50° C.), and the remaining orange solid is washed with diethyl ether (3×15 mL).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:11][S:10][C:9](=[S:12])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1.[I-:25].[Na+]>CC(C)=O.C(Cl)Cl>[I-:25].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][S:12][C:9]2[S:10][S:11][C:7](=[N+:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)=[CH:17][CH:16]=1
Reactant: S=c1cc(N2CCOCC2)ss1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)CSc2cc(=[N+]3CCOCC3)ss2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A suspension of 5-morpholino-1,2-dithiol-3-thione (2.62 g), 4-methoxyphenacyl bromide (4.12 g) and sodium iodide (3 g) in acetone (60 cc) is heated to the reflux temperature and maintained there for 2 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (30 cc), distilled water (2×40 cc) and acetone (2×30 cc). The product thus obtained is suspended in methylene chloride (110 cc). After stirring for 1 hour at a temperature of about 20° C., the insoluble product is separated by filtration. N-[5-(4-Methoxyphenacylthio)-1,2-dithiol-3-ylidene]-morpholinium iodide, melting at 152°-155° C., is thus obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].S(=O)(=O)(O)O.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)C>[CH2:29]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])[NH2:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CCCCCCCCCCCCO
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(=O)[C@@H](N)CCCNC(=N)N
Temperature: 140 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
A suspension of L-arginine free base (0.6 g, 3.5 mmol), sulfuric acid (0.31 ml, 7 mmol), and dodecanol (25 ml) were stirred together at 140° C. under nitrogen. After 6 hours, a clear light yellow solution resulted, and TLC indicated the reaction to be complete. The reaction mixture was diluted with diethyl ether (50 ml), and washed with water (3×25 ml). The combined aqueous extracts were washed with diethyl ether (2×25 ml), and basified with 1N KOH solution, upon which a white solid precipitated. Filtration of the suspension and washing of the filtrate with water (3× with 25 ml), acetone (3× with 25 ml) and diethyl ether (3× with 25 ml) gave arginine dodecyl ester. The yield was 86%. Melting point was 125-130° C. NMR gave the expected results for arginine dodecyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[C:27]([NH2:30])(=[O:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:30][C:27](=[O:29])[CH3:28])=[CH:3][CH:4]=2)=[N:9]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sccc2-3)cc1
Temperature: 100 °C
Yield: 71 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), acetamide (0.15 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give N-{4-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-acetamide as brown solid in 71% yield.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:19]1[N:28]=[C:27]([NH:29][CH2:30][C@H:31]2[O:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:19]3[N:28]=[C:27]([NH:29][CH2:30][C@H:31]4[O:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]4)[C:26]4[C:21](=[N:22][CH:23]=[CH:24][N:25]=4)[CH:20]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: C[Sn](C)(C)c1ccc(N2CCC(O)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(N4CCC(O)CC4)cc3)cc3nccnc23)C1
Yield: 27.6 %

Procedure:
1-(4-(trimethylstannyl)phenyl)piperidin-4-ol (398 mg, 1.17 mmol), (R)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (297 mg, 0.78 mmol), tetrakis(triphenylphosphine)palladium (180 mg, 0.15 mmol) were mixed in 5 mL toluene. The mixture was reacted at 100° C. overnight. Filtrated and concentrated, purified by flash chromatography (PE:EA=1:2) to give 112 mg reddish solid.
Reaction SMILES: [CH3:1][C@@H:2]1[N:25]([CH3:26])[CH2:24][C@:7]23[CH2:8][CH2:9][C@@H:10]4[C@@:15]5([CH3:23])[CH2:16][CH2:17][C@H:18]([N:20]([CH3:22])[CH3:21])[CH2:19][C:14]5=[CH:13][CH2:12][C@H:11]4[C@@H:6]2[CH2:5][CH2:4][C@H:3]13>C(OCC)(=O)C.[Pd]>[CH3:21][N:20]([CH3:22])[CH:18]1[CH2:19][CH:14]2[C:15]([CH3:23])([CH:10]3[CH:11]([CH2:12][CH2:13]2)[CH:6]2[CH2:5][CH2:4][CH:3]4[CH:2]([CH3:1])[N:25]([CH3:26])[CH2:24][C:7]24[CH2:8][CH2:9]3)[CH2:16][CH2:17]1
Reactant: C[C@H]1[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](N(C)C)CC[C@]5(C)[C@H]4CC[C@]23CN1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1C2CCC3C4CCC5CC(N(C)C)CCC5(C)C4CCC32CN1C
Yield: 29.9 %

Procedure:
Conessine (50 mg, 0.14 mmol) was dissolved in 3 mL ethyl acetate and 10% Pd/C (20 mg) was added under inert atmosphere. The reaction mixture was hydrogenated under a hydrogen balloon for 24 hours. Reaction was not complete by TLC. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated to give the crude product which was purified by silica gel column eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (15 mg, 30% yield).
Reaction SMILES: [C:1]([C:9]1[CH:30]=[CH:29][C:12]([NH:13][C@@H:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C@H:15]2[NH:23][C:24](OCC)=O)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([C:9]1[CH:30]=[CH:29][C:12]([NH:13][C@@H:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C@H:15]2[NH:23][CH3:24])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(C(=O)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.6 %

Procedure:
(±) trans 1-(4-Benzoylanilino)-2-ethoxycarbonylaminoindane (1.0 g, 2.50 mmol) was reduced with LiAlH4 (0.95 g, 25.0 mmol) as described for Example 2. After stirring at room temperature for 2 days, the reaction was worked up as described for Example 2. Purification on a silica gel column using 0-2% ethanol in chloroform as eluant afforded a solid (0.58 g) which was recrystallised to give the title compound as a colourless solid, m.p. 137°-138° C. (from methanol/diethyl ether/n-pentane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1OCCNC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
A mixture of 2-methoxyphenol (9.8 mL, 89.3 mmol), dimethylformamide (100 mL) and potassium carbonate (61.5 g, 445 mmol) was stirred at 23° C. while as tert-butyl 2-bromoethylcarbamate (20 g, 89.3 mmol) was added. The mixture was stirred for 24 hours and then poured into ethyl ether:hexanes (1:1, 400 mL) and was washed with water (5×50 mL). The aqueous layer was extracted with ethyl ether:hexanes (1:1, 3×40 mL) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to provide tert-butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.22 g, 97% yield) as a yellow oil; MS (PB-PCI) C14H21NO4 m/e calc 267.32; found 268 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[C:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[I-].[CH3:18][S+](C)(C)=O.[H-].[Na+]>>[CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]1[C:10]2([CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:18]1
Reactant: CC1=CCC(CC=C2CCCC2=O)C1(C)C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CC1=CCC(CC2CC23CCCC3=O)C1(C)C
Yield: 35.1 %

Procedure:
13.0 g (60 mmol) of 2-[2-(2,2,3-trimethylcyclopent-3-enyl)ethylidene]-cyclopentanone was cyclopropanated with 16.2 g (74 mmol) of trimethyl-sulfoxonium iodide and 3.6 g (75 mmol) of 50% oil suspension of sodium hydride according to Example 11a to give 4.9 g (35% yield) of 1-(2,2,3-trimethylcyclopent-3-enylmethyl)spiro[2.4]heptan-4-one.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([OH:17])(=[S:16])[CH3:15]>C(OCC)C>[C:14]([S:16][CH:10]([CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([OH:13])=[O:12])(=[O:17])[CH3:15]
Reactant: O=C(O)C=CC(=O)c1ccccc1
Reactant: CC(O)=S
Solvent: CCOCC
Product: CC(=O)SC(CC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.76 g of 3-benzoylacrylic acid in 30 ml of diethyl ether was added 0.8 ml of thioacetic acid, and the resulting mixture was stirred at room temperature for 5 hours. The diethyl ether was removed from the reaction mixture by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of hexane and dichloromethane as an eluent and recrystallized from a mixture of hexane and diethyl ether to give 2.09 g of 2-acetylthio-3-benzoylpropionic acid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:33])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:32])[F:31])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([N:21]([CH3:28])C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[F:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=1B(O)O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:34][C:4]1[S:3][C:2]([C:53]2[CH:54]=[C:49]([F:48])[CH:50]=[CH:51][C:52]=2[F:55])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:32])[F:31])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][CH3:28])[CH2:16][CH2:15]1)=[O:33]
Reactant: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2CC(F)F)CC1
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CN[C@@H]1CCCN(c2c(NC(=O)c3nc(-c4cc(F)ccc4F)sc3N)cnn2CC(F)F)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of (R)-tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoro-N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (200 mg, 0.29 mmol), Na2CO3 (62 mg, 0.59 mmol) and 2,5-difluorobenzeneboronic acid (66 mg, 0.41 mmol) in DME (3 mL) and water (1 mL) was degassed by gently bubbling nitrogen through the mixture for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (30 mg, 0.037 mmol) was then added and the mixture heated in a microwave at 120° C. for 60 min. The solvents were removed under reduced pressure and the residue dissolved in a solution of HCl in 1,4-dioxane (4 M, 5 mL) and MeOH (5 mL) and stirred at 70° C. for 48 hr. The solvent was removed under reduced pressure and the residue dissolved in MeOH/DCM and passed through an SCX cartridge washing with DCM and MeOH and eluting with 1 N ammonia in MeOH. The solvent was removed under reduced pressure and the residue purified by preparative HPLC to yield 108 as the mono formate salt as a pale brown solid (21 mg, 14% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.53 (s, 1H), 8.15-7.95 (m, 1H), 7.58 (s, 1H), 7.35-7.05 (m, 2H), 6.25 (tt, J=55.6, 4.1 Hz, 1H), 4.54-4.43 (m, 2H), 3.43-3.22 (m, 5H), 2.68 (s, 3H), 2.28-1.74 (m, 6H). LCMS (ES+) m/z 512 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[N:6][CH:7]=1.[OH-].[K+].Br[CH2:16][CH2:17][OH:18]>C(O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH2:16][CH2:17][OH:18])[N:12]=2)=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: Brc1ccc(-c2nn[nH]n2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: OCCn1nnc(-c2ccc(Br)cn2)n1
Temperature: 80 °C
Yield: 26.4 %

Procedure:
5-Bromo-2-(2H-tetrazol-5-yl)pyridine (WO 0194342 A1) (1.2 g, 5.3 mmol) was dissolved/suspended in 1-propanol (15 ml), a solution of potassium hydroxide (250 mg, 4.5 mmol) in 1-propanol (15 ml) was added and it was heated at 80° C. for 1 hour. 2-Bromoethanol (0.344 ml, 4.8 mmol) was added and it was refluxed for one day. Further potassium hydroxide (270 mg) and 2-bromoethanol (0.35 ml) were added and the mixture was heated for another 4 hours at reflux. Further potassium hydroxide and 2-bromoethanol were added once more and the mixture was refluxed for 14 hours. The reaction mixture was filtered through a 0.45 μM membrane and the filter cake was washed with ethanol and dichloromethane. Chromatography on silica gel with hexanes/ethyl acetate 1:1 to ethyl actetate gave 0.342 g of the title compound (24%), together with 0.225 g of the corresponding 1H-tetrazole regioisomer.