Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[Cl:21][C:22]([Cl:31])([Cl:30])[CH2:23][O:24][C:25](=[O:29])/[CH:26]=[CH:27]/[CH3:28].C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Cl:21][C:22]([Cl:30])([Cl:31])[CH2:23][O:24][C:25](=[O:29])/[CH:26]=[CH:27]/[CH2:28][Br:1]
Reactant: C/C=C/C(=O)OCC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(/C=C/CBr)OCC(Cl)(Cl)Cl
Yield: 75 %

Procedure:
The bromination reaction takes place in carbon tetrachloride with N-bromosuccinimide and AIBN as radical former. For this purpose, an equimolar amount of ester (i) and 0.45 mole N-bromosuccinimide are mixed with 300 ml. carbon tetrachloride and a spatula tip of AIBN added thereto. The reaction mixture is heated under reflux for 4 hours, subsequently allowed to cool and the precipitated succinimide (0.41 mole; 92% of theory) is filtered off. After distilling off the solvent in a vacuum, the residue is purified by column chromatography using PE/PE (25:1 v/v) as elution agent. The end product obtained is a yellow oil. The yield of 75% of theory. C6H6O2BrCl3 (296.3752 g./mole).
Reaction SMILES: [CH2:1]([N:3]([C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:22][CH2:21]1
Reactant: CCN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrCCCCBr
Product: CCN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-Ethyl-N-(4-hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide and 1,4-Dibromobutane were converted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide as colorless oil, MS 470 (M—CH3,1Br).
Reaction SMILES: C1CCCCC1.S(=O)(=O)(O)O.O=O.[N+:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23])([O-:16])=[O:15].[N+:24](C1CCCCC1)([O-:26])=[O:25]>C(Cl)(Cl)(Cl)Cl>[N+:24]([O-:26])([O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N+:14]([O-:16])=[O:15])=[O:25]
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: O=[N+]([O-])C1CCCCC1O
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=[N+]([O-])OC1CCCCC1[N+](=O)[O-]
Yield: 30 %

Procedure:
A solution of 4.4 grams (50 mmoles) of cyclohexane in 50 milliliters of carbon tetrachloride containing 1 milliliter of concentrated sulfuric acid was treated with 6.9 grams of N2O4 and 21 grams of oxygen at about 5°C. Analysis of the isolated product (7.3 grams) showed it consisted of a mixture of 2-nitrocyclohexyl nitrate (30 percent yield), 2-nitrocyclohexanol, nitrocyclohexane and carboxylic acids.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: Clc1nccc2cnccc12
Product: c1cc2c(N3CCOCC3)nccc2cn1

Procedure:
To 1-chloro-2,6-naphthyridine (164.3 mg, 0.998 mmol) (prepared as described in Van den Haak et al, J. Org. Chem 1982, 47 (9), 1673–7) was added morpholine (15 mL) and the mixture was heated at reflux for 4 h. Removal of the volatile components gave 216.6 mg of 1-morpholin-4-yl-[2,6]naphthyridine as a beige solid.
Reaction SMILES: [C:1]1([C:7]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])[C:8]([CH:10]([C:16](OCC)=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O>[OH:17][C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:7]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])[C:8](=[O:9])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCC1(CCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
The product of Example 1E (4.51 g, 12.4 mmol) was treated with concentrated sulfuric acid (25 mL) and stirred at 25° C. for 3 hours. The mixture was then poured into a mixture of ice and water (500 mL) and stirred until all the ice melted. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with water and saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with methyl t-butyl ether in hexane to afford the title compound (1.73 g, 44%). 1H NMR (300 MHz, CDCl3): δ 15.15 (d, J=13.24 Hz, 1 H), 8.18 (m, 1 H), 7.59 (m, 1 H), 7.40 (m, 2 H), 4.47 (m, 2 H), 2.25 (m, 2 H), 1.91 (m, 1H), 1.70 (m, 1 H), 1.47 (q, J=7.23 Hz, 3 H), 1.25 (m, 1 H), 0.93 (m, 2 H), 0.67 (m, 7 H).
Reaction SMILES: C([N:3](CCCC)[C:4](=[O:6])[CH3:5])#N.[CH2:11]([N:13]([CH2:16][CH2:17][CH2:18]N)[CH2:14][CH3:15])[CH3:12]>O1CCCC1>[CH2:14]([N:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH2:5][C:4]([NH2:3])=[O:6])[CH3:15]
Reactant: CCN(CC)CCCN
Reactant: CCCCN(C#N)C(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCCCC(N)=O

Procedure:
12.60 g (0.09 mol) of N-cyano-N-butylacetamide are refluxed with 13.4 g (0.1035 mol) of diethylaminopropylamine in 25 ml of tetrahydrofuran for 2 hours, after which, according to investigation by gas chromatography, the educt has completely reacted to give 3-diethylaminopropylacetamide, tri-n-butylisomelamine and another component, which probably consists of butyl cyanamide. The mixture is concentrated on a rotary evaporator, and the oil which remains is left to stand at room temperature and the reaction which subsequently takes place is monitored by gas chromatography. After 5 days, the unknown component, which probably consists of butyl cyanamide, has largely reacted and has formed tributylisomelamine by trimerisation. The mixture is distilled in a bulb tube oven, first under 23.4 mbar and at a maximum temperature of 125° C. and then under 0.156 mbar and at a maximum temperature of 180° C. 6 fractions totalling 24.4 g are thereby obtained, analysis of which by gas chromatography gives a yield of 74.7% of tributylisomelamine and 96.7% of 3-diethylaminopropylacetamide. An analysis sample of tributylisomelamine, which is liquid at room temperature, can be isolated by renewed distillation of the fractions obtained under the high vacuum.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:16]([C:19]([CH3:26])([NH2:25])[C:20]#[C:21][C:22]([OH:24])=O)[CH:17]=[CH2:18].[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:45])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>O1CCCC1.N1C=CC=CC=1>[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:45][C:22](=[O:24])[C:21]#[C:20][C:19]([CH2:16][CH:17]=[CH2:18])([CH3:26])[NH2:25])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: C=CCC(C)(N)C#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCC(C)(N)C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Isobutyl chloroformate (0.845 g, 6.2 mmol) and N-methylmorpholine (1.0 g, 9.9 mmol) were added to an ice cold solution of 1.53 g (10.0 mmol) of allyl-methyl-amino-but-2-ynoic acid in 100 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, then it was poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (5:95), gave 0.750 g of allyl-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 450.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[C:4]([C:17]2[C:25]3[C:20](=[C:21]([O:26][CH3:27])[N:22]=[CH:23][CH:24]=3)[N:19]([CH3:28])[CH:18]=2)[CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O1CCOCC1>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][C:4]=2[C:17]2[C:25]3[C:20](=[C:21]([O:26][CH3:27])[N:22]=[CH:23][CH:24]=3)[N:19]([CH3:28])[CH:18]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: CS(=O)(=O)Cl
Reactant: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(C#N)cc3)cn(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1nccc2c(-c3cc(NS(C)(=O)=O)ccc3Oc3ccc(C#N)cc3)cn(C)c12
Temperature: 80 °C

Procedure:
A mixture of Example 16D (0.03 g, 0.081 mmol), methanesulfonyl chloride (0.028 g, 0.243 mmol), and triethylamine (0.049 g, 0.486 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 2 hours. The solvent was removed, and the residue was treated with sodium hydroxide (0.656 mL, 1.31 mmol) and dioxane (3 mL). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[CH3:14][C:15]([CH3:19])=[CH:16]CBr.[CH2:20](O)C>>[CH2:2]([O:4][C:5](=[O:13])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:20])[CH2:12][CH:14]=[C:15]([CH3:19])[CH3:16])[CH3:3]
Reactant: CCO
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(C)(CC=C(C)C)C(=O)OCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
36.1 g of sodium (cut into small pieces) was introduced into a three-necked flask equipped with reflux condenser, dropping funnel, and agitator. To this mixture was added 800 ml of absolute ethanol so quickly that the solution continued to boil vigorously. The hot alcoholate solution was combined dropwise with 269.6 g of freshly distilled methylmalonic acid diethyl ester, the mixture was stirred for 1/2 hour at 60° C. and then 241.7 g of dimethylallyl bromide was also added dropwise thereto. After one hour of agitation under heating, the thus-precipitated sodium bromide was filtered off, the precipitate was washed, and the filtrate was concentrated. The remainder was taken up in ether, washed neutral with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated on a forced circulation evaporator. The evaporation residue was fractionated on an oil pump, yielding 266 g of the title compound, bp7 97°-112° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:24][N:10]([CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][O:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:4][CH2:5]1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide is treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexylmethyl ester as colorless solid, MS: 443 (M+).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[O:36])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1
Reactant: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](NC(=O)C4CCOCC4)CC3)CC2)n1

Procedure:
The title compound, off-white solid (128 mg, 94%), MS (ISP) m/z=455.4 [(M+H)+], mp 219° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate D) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1.CC(O)C.[OH-].[K+]>O>[NH2:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=2)[N:17]=1
Reactant: Nc1ccc2cc(C(=O)OCc3ccccc3)ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc2cc(C(=O)O)ccc2n1
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 2-amino-quinoline-6-carboxylic acid benzyl ester (15.63 g, 0.0562 moles), 2-propanol (235 mL), water (15.6 mL) and potassium hydroxide (6.3 g, 0.112 moles) was heated to reflux, 80° C. to 85° C., for 2 to 4 hours. The reaction mixture was then cooled to 20° C. to 25° C., vacuum concentrated (volume of 160 mL) and granulated at 20° C. to 25° C. for 8 to 16 hours. The product was isolated by filtration (12.08 g, 0.0534 moles, 95% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[NH:7].[CH:9](=[C:16]([C:19]#[N:20])[C:17]#[N:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N=C(N)c1cccs1
Reactant: N#CC(C#N)=Cc1ccccc1
Product: NCc1c(N)nc(-c2cccs2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=282.8 (M+H+), was prepared from thiophene-2-carboxamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=[O:14])=[CH:9][NH:10][C:3]=2[CH:2]=1.CS(C)=O.[O:21]=[C:22]1[NH:30][CH:29]=[N:28][C:27]2[N:26]([CH2:31][CH2:32][C:33](OC3C=CC([N+]([O-])=O)=CC=3)=[O:34])[CH:25]=[N:24][C:23]1=2>CC(C)=O>[O:21]=[C:22]1[NH:30][CH:29]=[N:28][C:27]2[N:26]([CH2:31][CH2:32][C:33]([NH:16][CH:12]([CH2:11][C:8]3[C:4]4[C:3](=[CH:2][CH:1]=[C:6]([OH:7])[CH:5]=4)[NH:10][CH:9]=3)[C:13]([OH:15])=[O:14])=[O:34])[CH:25]=[N:24][C:23]1=2
Reactant: NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7.3 %

Procedure:
100 mg (0.500 mmol) of DL-5-hydroxytryptophan and 3 ml of dry dimethylsulfoxide were placed in a 25 ml round bottom flask equipped with a magnetic stirring bar and stopper. Then 150 mg (0.456 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) were added and the heterogeneous mixture was stirred for 2.5 hours at room temperature in the closed flask. The mixture became completely homogeneous. The reaction mixture was poured into 20 ml of acetone and a semi-solid precipitate was obtained by filtration. The crude product was washed twice with 2 ml of acetone. The solid was resuspended in 10 ml of acetone and the insoluble material was removed by filtration. The acetone solution was evaporated to dryness. The yield of product 2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-3-(5-hydroxyl-1H-indol-3-yl)-propionic acid (AIT-0111) was 15 mg. Yield: 7.3% (Purity 93 %).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[CH:18]12[O:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]2.B(F)(F)F.CCOCC>CCOCC.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[OH:24])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: C1CCC2OC2C1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1CCCCC1c1cc(F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 8.00 g (32.9 mmol) 3-fluoro-5-trifluoromethyl-bromo-benzene in 40 ml Et2O under nitrogen was cooled to −78° C. and drop-wise 20.56 ml (32.9 mmol) of a 1.6 M butyl lithium solution in hexane were added. The reaction was strongly exothermic and the temperature was kept below −70° C. Then after 30 min. at −78° C. 2.66 ml (2.58 g, 26.3 mmol) cyclohexene oxide were added followed by 3.75 ml (4.2 g, 29.6 mmol) boron trifluoride diethyl etherate. The latter has to be added drop-wise to keep the temperature below −70° C. The reaction mixture was stirred for 2 h at −78° C. and then quenched with 40 ml saturated aqueous KHSO4 solution, warmed up to ambient temperature and extracted with tert.-butyl methyl ether. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product, 7.53 g light yellow crystals, was purified by re-crystallisation from n-heptane: 4.90 g rac-2-(3-fluoro-5-trifluoromethyl-phenyl)-cyclohexanol as colorless crystalls: m.p. 76.5–77.4° C., MS (EI): 262.1 M+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[C:17]([N:19]([CH2:22]C)[CH2:20]C)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH:34]=O)=[C:27]([O:36][C:37]([F:40])([F:39])[F:38])[CH:26]=1.C(O)(=O)C.[BH3-]C#N.[Na+].[ClH:49]>CO.CCOC(C)=O>[ClH:49].[ClH:49].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]3[N:18]=[C:17]([N:19]([CH3:20])[CH3:22])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:4][CH2:3]2)=[C:27]([O:36][C:37]([F:38])([F:39])[F:40])[CH:26]=1
Reactant: CCN(CC)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Reactant: O=CCCCc1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCCCCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step C of example 9 (240 mg, 0.84 mmol) in MeOH (3 mL) were added 4-(4-bromo-2-trifluoromethoxy-phenyl)-butyraldehyde (262 mg, 0.84 mmol), acetic acid (79 mg, 1.26 mmol), and NaBH3CN (79 mg, 1.26 mmol). The reaction mixture was stirred at ambient temperature for 8 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give a pale yellow solid. To a solution of above solid in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. A solution of the residue in Et2O (20 mL) was stirred at ambient tempareture for 1 hr. The solid was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-{4-[4-(4-bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride (220 mg, 40%) as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:11]([C@@H:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)=[O:12])[CH2:24]2)[CH:18]=1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Reactant: COC(=O)c1cccc(C2CCCNC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc([C@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (240 mg, 1.21 mmol) in DCM (5 ml) was added to an ice-cold mixture of 3-(piperidin-3-yl)benzoic acid methyl ester (267 mg, 1.21 mmol), triethylamine (59 mg, 0.58 mmol) and DCM (10 ml). After stirring for 2 h at RT, the mixture was washed with 1 M HCl (10 ml) and 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated to dryness and the residue was purified by flash chromatography using heptane/EtOAc as eluent. The first eluting diastereomer was collected to afford 98 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]OC(=O)C)[CH:8]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=1[OH:20])([CH3:4])([CH3:3])[CH3:2].[C:21]1([CH3:29])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1.S(=O)(=O)(O)O.[C:35]([OH:38])(=O)[CH3:36]>>[CH3:29][C:21]1[C:26]([CH2:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:6]([OH:20])=[C:7]([C:16]([CH3:18])([CH3:19])[CH3:17])[CH:8]=2)=[C:25]([CH3:27])[C:24]([CH2:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:20])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=2)=[C:23]([CH3:28])[C:22]=1[CH2:11][C:9]1[CH:10]=[C:36]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:35]([OH:38])=[C:7]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:8]=1
Reactant: Cc1cc(C)cc(C)c1
Reactant: CC(=O)OCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C

Procedure:
To an acetic acid solution of 73 g of the thus produced product comprising 2,6-di-tert-butyl-4-acetoxymethylphenol (85.5% by GC) was added mesitylene (2.4 g) and sulfuric acid (2 g, 98%); the resulting solution was heated at 60° C. for six hours. Most of the acetic acid was removed under reduced pressure and 65-70° C.; the resulting paste was dissolved in heptane (120 g); and the resulting solution was washed with water (2×60 g) at 70-75° C. The solution was dried by azeotropic removal of water and cooled to ambient temperature; 1,3,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)benzene was isolated as an off-white solid (8.1 g).
Reaction SMILES: C(OC1N=CC=CC=1C(O)=O)CCC.C(N(CC)CC)C.COC(Cl)=O.Cl.[CH2:28]([O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35](CCN)=[CH:34][CH:33]=1)[CH3:29]>O1CCCC1>[CH2:28]([O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(CCN)cc1
Agent: CCCCOc1ncccc1C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.5 g of 2-butoxy-nicotinic acid (melting point= m.p. 54°-56° C., from acetic acid ethyl ester) are dissolved in 150 ml of tetrahydrofuran. After addition of 14.5 ml of triethylamine, the batch is cooled to 0° C., and 3.2 ml of chloroformic acid methyl ester are added dropwise. Agitation is continued for one hour at 0° C., 7.6 g of 4-(2-aminoethyl)-benzoic acid ethyl ester-hydrochloride are added, agitation is continued for a further hour at 0° C., and subsequently for 4 hours at room temperature. The batch is evaporated and the residue is combined with acetic acid ethyl ester. After washing with water, sodium bicarbonate solution, dilute hydrochloric acid and water, the acetic acid ethyl ester solution is dried and evaporated under reduced pressure. The 4-(2-<2-butoxy-nicotin-amido>-ethyl)-benzoic acid ethyl ester so obtained is refluxed for 3 hours in 25 ml of 2 N sodium hydroxide solution and 50 ml of ethanol. After having distilled off the solvent, the product is dissolved in water and acidified with dilute acetic acid, suction-filtered and recrystallized from acetic ester. The 4-(2-<2-butoxy-nicotin-amido>-ethyl)-benzoic acid has a melting point of 147°-149° C.