Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Si:6]([O:13][C@@H:14]1[C@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:17]([CH2:27][O:28][CH3:29])[O:16][C@H:15]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([CH2:54][OH:55])=[N:34][C:35]=2[NH:39][CH2:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:55][CH2:54][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[C@H:15]2[C@H:14]([O:13][Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:7])[CH3:8])[C@H:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21])[C@@H:17]([CH2:27][O:28][CH3:29])[O:16]2)=[C:35]([NH:39][CH2:40][CH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:34]=1)(=[O:4])=[O:3]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CO)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Methanesulfonyl chloride (0.6 ml, 7.7 mmol) was slowly added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methanol (4.22 g, 5.87 mmol) (preparation 15) and triethylamine (1.2 ml, 8.62 mmol) in dichloromethane (50 ml) and the mixture stirred at room temperature for 30 minutes. Triethylamine (1 ml, 7.2 mmol) and methanesulfonyl chloride (0.5 ml, 6.4 mmol) were then added and stirring continued for a further 15 minutes. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (1:3) changing to ethyl acetate:pentane (1:1) to afford the title compound as a gum (4.52 g). MS: 820 (MNa+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:2][CH2:3][CH3:4].[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(F)cc1CCC(=O)O
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1ccc(F)cc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 4.4 %

Procedure:
A solution of 3-(2-butoxy-5-fluoro-phenyl)-propionic acid (300 mg, 1.37 mmoles) and benzoic acid N′-isopropyl-hydrazide (203 mg, 1.14 mmoles) in DMF (3 mL) was treated with diisopropylethylamine (0.50 mL, 2.85 mmoles), and PyBroP (800 mg, 1.71 mmoles) at room temperature for 16 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (20 mg, 5%). LC-MS m/e 401.28 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:17]N1C(=O)CCC1=O.O>ClCCl>[Br:17][C:10]1[N:9]=[C:8]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: Cc1nccn2c(C3CCOCC3)ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: Cc1nccn2c(C3CCOCC3)nc(Br)c12
Temperature: 50 °C
Yield: 93.5 %

Procedure:
To a solution of 8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (0.888 mmol, 193 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (0.888 mmol, 158 mg) and the reaction mixture was heated at 50° C. (bath temperature) for 15 min. Dichloromethane and water were added, the organic layer separated, washed with an aqueous sodium hydrogencarbonate solution, dried (sodium sulfate) and concentrated in vacuo to afford 246 mg of 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:23])=[CH:13][N:12]([CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:11]1=[O:33])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:47](Br)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:19][C:18]2=[O:23])=[CH:13][N:12]([CH2:24][C:25]2[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=2[F:31])[C:11]1=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCNCC2=O)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3ccccc3)CC2=O)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of {(R)-2-[3-(2,6-difluoro-benzyl)-2,6-dioxo-5-(2-oxo-piperazin-1-yl)-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (7) (20 mg, 0.036 mmol) in DMF (1 mL) were added potassium carbonate (12 mg, 0.09 mmol) and benzyl bromide (7 mg, 0.040 mmol) in that order, followed by stirring at room temperature for 1 hr. The solution was diluted with dichloromethane and washed with distilled water. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 22 mg of the compound as a white solid (yield 96%). 1H NMR (300 MHz, CDCl3) δ 1.32 (9H, s), 2.86 (2H, t), 3.32 (2H, s), 3.58 (2H, m), 3.73 (2H, s), 4.04 (1H, m), 4.46 (1H, t), 5.05 (3H, m), 5.53 (1H, m), 6.98 (2H, t), 7.24-7.38 (6H, m), 7.56 (2H, m), 7.71 (1H, d), 8.20 (1H, dd), 8.26 (1H, s)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18].Cl[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)O)cn2c1=O
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)OCCN(CC)CC)cn2c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.6 g) was reacted with 1-chloro-2-(diethylamino)ethane (2.7 g) and anhydrous K2CO3 (2.8 g) in dimethylformamide (40 ml) under stirring at 50° C. for 8 hours. After dilution with water, the precipitate was filtered off and washed with water until neutral: crystallization from isopropyl ether gave 2.1 g of 2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, 2-diethylamino-ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH2:15][CH2:16]C3C=CC=CC=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH2:15][CH2:16][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c(-c2ccccc2)noc1CCc1ccccc1
Reactant: BrCc1ccccc1
Product: O=C(O)c1c(-c2ccccc2)noc1CCCc1ccccc1
Yield: 72 %

Procedure:
The title compound was prepared as described for Compound 28A but substituting 2-phenylethylbromide for benzyl bromide. The crude was purified by flash chromatography (ethyl acetate-petroleum ether-acetic acid 1:1:0.01 mL) to afford the title compound (72%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:25][C:26]3[N:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:25][C:26]3[N:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc([N+](=O)[O-])ccc23)n(C(C)(C)C)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc(N)ccc23)n(C(C)(C)C)n1
Yield: 66.7 %

Procedure:
2.00 g of 7-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one were hydrogenated over palladium on charcoal in MeOH/THF 1:1 at RT. After completion of the reaction the catalyst was filtered off and the filtrate evaporated. The residue was dissolved in 50 ml DCM and extracted three times with a 3:1 mixture of water/conc. HCl. The combined aqueous phases were brought to pH 8 by addition of sodium bicarbonate and extracted with DCM. Removal of the solvent yielded 1.25 g of the title product.
Reaction SMILES: C[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11](C)[CH2:12][C:13]([OH:15])=[O:14])CC(O)=O.[CH3:17]C(=O)CCCCC(=O)C.BrC[C:29]([O:31]CC)=[O:30].CC(C(OCC)=O)C(OCC)=O.BrCCCCBr>>[CH3:17][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([CH3:2])[C:29]([OH:31])=[O:30])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)CCCCC(C)=O
Reactant: CC(CCCCC(C)CC(=O)O)CC(=O)O
Agent: CCOC(=O)C(C)C(=O)OCC
Solvent: BrCCCCBr
Product: CC(CCCCC(C)C(=O)O)C(=O)O

Procedure:
As processes for synthesizing 3,8- or 3,7-dimethyldecanedioic acid, the following (7) through (9) are known: (7) a process for synthesizing 3,8-dimethyldecanedioic acid, from 2,7-octanedione comprising the five steps of Reformatsky reaction of ethyl bromoacetate, bromination of hydroxyl group, dehydrobromination, hydrogenation of double bond and hydrolysis of ester (see Ann., 580, 125-131 (1953)); (8) a process for synthesizing 3,8-dimethyldecanedioic acid, comprising seven steps starting from malonic condensation of diethyl methylmalonate and 1,4-dibromobutane, followed by hydrolysis and decarboxylation to obtain 2,7-dimethyloctanedioic acid as an intermediate and the subsequent conversion of this intermediate to acid chloride, which is then converted via diazoketone into the intended dicarboxylic acid (see Ann., 598, 1-24 (1956)); (9) a process to obtain 3,7-dimethyldecanedioic acid by hydrogenation of essential oil of Geranium macrorhizum, and subsequent ozonolysis and degradation with perchloric acid (see Chem.listy, 52, 1174-1179 (1958)).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(CCCCC(O)=O)=[O:10].N.[H][H]>O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:10]
Reactant: O=C1CCCCCN1
Reactant: [H][H]
Reactant: O=CCCCCC(=O)O
Agent: N
Solvent: O
Product: NCCCCCC(=O)O

Procedure:
Finally, DE-A-No. 3,602,377 discloses a process for preparing caprolactam wherein the 5-formylvaleric ester is initially hydrolyzed with water in the presence of a catalyst from 30° to 200° C. to 5-formylvaleric acid which is reacted with ammonia and hydrogen in the presence of a solvent and hydrogenation catalyst under a superatmospheric pressure at from 50° to 150° C. to give 6-aminocaproic acid, the ammonia and the catalyst are separated off, and the resulting solution of 6-aminocaproic acid is heated to 150°-370° C. to form caprolactam. For this process to be practised in industry, the yields must be improved. Moreover, this process requires an additional hydrolysis stage.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:36][CH3:37])(=[O:35])[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(OCC)(=O)C>CS(C)=O.O>[C:21]([C:9]1[C:7]2[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:5][C:6]=2[C:12]([CH:30]([C:29]([O:36][CH3:37])=[O:35])[C:31]([O:33][CH3:34])=[O:32])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[CH3:20])#[N:22]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C(=O)OC)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 90 °C
Reaction time: 14 h
Yield: 77.4 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (2.69 g, 9.20 mmol) was dissolved in dimethyl sulfoxide (50 ml), then at room temperature, potassium carbonate (3.82 g, 27.61 mmol) and dimethyl malonate (2.1 ml, 18.41 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 14 hours. The reaction liquid was cooled to room temperature, then ethyl acetate and water were added to the reaction liquid, followed by vigorously stirring for 10 minutes. The aqueous layer was separated, extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=3:1, v/v) to obtain the entitled compound (2.878 g, 77%) as a colorless gel
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13](Br)[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1C(=O)CCC1.C([Cu])#N.O>CCOC(C)=O>[CH2:1]([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13]([C:35]#[N:36])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(Br)c21
Agent: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(C#N)c21
Temperature: 190 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
A 500 mL RBF was charged with 5-bromo-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester (12.00 g, 23 mmol), NMP (100 mL), and CuCN (20.34 g, 0.227 mol). The reaction was heated to 190° C. with vigorous stirring for 45 minutes. The reaction was then cooled to ambient temperature, diluted with EtOAc followed by water (300 mL). A 1:1 mixture of Celite/silica gel were added to the mixture. This suspension was stirred for several minutes and filtered through a pad of Celite. The Celite pad was washed with EtOAc, and the filtrate was washed with water (5×) and saturated NaCl (1×), dried over MgSO4, and concentrated. Upon trituration with hexanes, 8.82 g (81.8%) of a light tan solid was obtained. 1H NMR (CDCl3) δ 10.11 (br s, 1H), 8.12 (s, 1H), 7.40 (m, 5H), 5.37 (s, 2H), 4.22 (m, 2H), 3.95 (m, 2H), 3.00 (m, 4H), 2.83 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.89 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:44][C:45]1[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:44][C:45]1[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=1)=[O:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: Cc1nc(N)sc1C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nc(C)c(C)s4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-4,5-dimethylthiazole hydrochloride (50 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 33 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([CH3:16])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=2)[CH2:4][CH2:3]1.O=O.O.C([O:25]C)(C)(C)C>C(O)(=O)C>[CH3:17][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([CH3:16])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=2)[C:4](=[O:25])[CH2:3]1
Reactant: COC(C)(C)C
Reactant: CCCCOc1cc2c(cc1C)CCC2(C)C
Agent: O=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1cc2c(cc1C)C(=O)CC2(C)C
Temperature: 40 °C
Yield: 75.5 %

Procedure:
100 g 3,3,6-trimethyl-5-butoxy-indane are dissolved in 400 g acetic acid and 1 g Co-II acetate is added. The reaction mixture is heated to 40° C., with stirring, and oxygen is passed through this solution for 10 hours. After cooling to room temperature, 500 g water and 500 g methyl tert.-butyl ether are added. After phase separation, the organic phase is rinsed with a further 200 g water and distilled in a 30 cm packed column. 80 g 3,3,6-trimethyl-5-butoxy-indan-1-one is obtained, which corresponds to a yield of 75% of theory. The compound can be recrystallised from heptane and a white solid is obtained, melting point: 59° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([C:18](OC)=[O:19])[CH:11]=[C:12]([CH:17]=2)[C:13](OC)=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1.CC(C[Al]CC(C)C)C>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:12]([CH2:13][OH:14])[CH:11]=[C:10]([CH2:18][OH:19])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2c(C)ccc2C)c1
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(CO)cc(CO)c1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 9 (2.87 g, 10 mmol) in THF (60 mL) at −78° C. was added Dibal-H (1 M solution in toluene, 60 mL, 60 mmol) drop wise. The reaction mixture was slowly warmed to room temperature over a period of 6 h, and then quenched by sodium potassium tartrate (1 M, 40 mL) The THF was removed by rotary evaporation, and the resulting aqueous solution was extracted by ether (3×100 mL) The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes, 2:1-4:1) to yield 10 (2.24 g, 97%) as a white solid (Caution: the product is not stable as solution forms, while stable in solid form for weeks at room temperature): 1H NMR (500 MHz, CDCl3) δ 2.01 (s, 6H), 2.45 (s, 2H), 4.69-4.70 (d, J=5.5 Hz, 4H), 5.89 (s, 2H), 7.10 (s, 2H), 7.39 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.1, 64.5, 105.8, 124.3, 125.6, 128.7, 139.3, 142.4; LC-MS (M+H+) calcd for C14H18NO2 232, found 232.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[CH:22]=4)[NH:17]3)=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([OH:30])=[O:29])[CH:22]=4)[NH:17]3)=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCCCC3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)C2CCCCC2)cc1
Yield: 95 %

Procedure:
To a mixture of methyl 2-(4-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (53 mg, 0.11 mmol) in methanol (3 mL) and water (1.5 mL) was added a solution of sodium hydroxide (123 mg, 2.83 mmol.) in water (1.5 mL). The resultant mixture was heated for reflux until the complete of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-(cyclohexanecarboxamido) phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, yellow solid, 50 mg, 95% Yield; MS (ESI+APCI) M+1=429.11.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].CC(=CCC/C(=C/C=O)/C)C.CC(=CCC/C(=C\C=O)/C)C>>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=O
Agent: CC(C)=CCC/C(C)=C/C=O
Agent: CC(C)=CCC/C(C)=C\C=O
Product: CC(C)=CCCC(C)CC=O

Procedure:
A-8) asymmetrically hydrogenating citral containing geranial and neral at a molar ratio of from 90:10 to 10:90 to thereby obtain an optically active citronellal having an optical purity of from 70 to 99% e.e.,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([F:21])([F:20])C(O)=O.O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:16]([F:21])[F:20])[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
A mixture of 5-bromopyridin-3-ol (3.7 g, 21 mmol) and potassium carbonate (8.8 g, 64 mmol) in DMF (50 ml) was treated with 2-chloro-2,2-difluoroacetic acid (2.16 ml, 25 mmol) and the reaction mixture was heated at 100° C. overnight. Further potassium carbonate (4.4 g, 32 mmol) and 2-chloro-2,2-difluoroacetic acid (1.08 ml, 12.5 mmol) were added and the reaction mixture stirred at 100° C. overnight. Water and ethyl acetate were added and the organic phase was washed with brine, dried over magnesium sulphate and the solvent was removed under vacuum. The resulting crude was purified by flash chromatography using SP1® Purification System (0% to 15% in 25 CV, hexane-ethyl acetate) to obtain 0.81 g (17% yield) of the title compound. Purity: 100%