Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:42][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:31][CH:30]=1)[CH2:42][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)CCc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonylethyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 14 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][C:8]([N:11]1[C:19]2[C:18]([F:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:13](I)=[CH:12]1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:29](=[N:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([CH:54]=1)[C:48](N(OC)C)=[O:49])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[C:29](=[N:42][C:43]1[CH:54]=[C:47]([C:48]([C:13]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=3[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:23])[CH3:22])[CH:12]=2)=[O:49])[CH:46]=[N:45][CH:44]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncc(F)c21
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncc(F)c21
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a stirring solution of 1-[2-(tert-Butyl-dimethyl-silyloxy)-1,1-dimethyl-ethyl]-7-fluoro-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 73, 3 g, 6.69 mmol) in dry ether (100 mL) at −78° C., n-BuLi (3.9 mL, 1.84M, 7.17 mmol) was added and stirred for 30 minutes. Then 5-(benzhydrylidene-amino)-N-methoxy-N-methyl-nicotinamide (Preparation 52, 2.31 g, 6.69 mmol) in dry ether (10 mL) was added drop wise for 5 min. After 1 hr reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated in vacuo to afford the crude compound, purified by silica gel column chromatography eluting with Ethyl acetate: Hexane 30:70 to 35:65 to afford the title compound as a light red solid (25%, 1 g).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO>[CH:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[NH2:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: O=C(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of crude cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanone (505 mg, 1.51 mmol), and ammonium acetate (1.19 g, 15.1 mmol) in methanol (7.6 ml) was added sodium cyanoborohydride (0.150 g, 2.26 mmol). The flask was fitted with a reflux condenser and heated to reflux for 12 hours. The reaction was concentrated in vacuo, then diluted with dichloromethane and aqueous 1.0M sodium hydroxide. The mixture was stirred for 30 minutes, whereupon the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was diluted in dichloromethane, passed through a plug of SiO2 with 20% methanol in dichloromethane and was concentrated in vacuo. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([Cl:15])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:28]([C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([CH:37]=O)[CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])C.[OH-].[K+].Cl>C(O)C>[CH:39]1([N:27]2[C:26]3[CH:45]=[CH:46][C:23]([C:21]([OH:22])=[O:20])=[CH:24][C:25]=3[N:29]=[C:28]2[C:30]2[CH:31]=[C:32]3[C:33](=[CH:34][CH:35]=2)[N:36]=[C:12]([C:11]2[C:6]([C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:7][CH:8]=[C:9]([Cl:15])[CH:10]=2)[CH:13]=[CH:37]3)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Reactant: CC(=O)c1cc(Cl)ccc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Cl)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
1-(4′-Chloro-4-chloro-biphen-2-yl)-ethanone (132 mg, 0.5 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 132 mg product.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)CC2CCN(C(C)=O)CC2)cc1
Agent: Cl
Product: COc1ccc(C(=O)CC2CCNCC2)cc1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of 10 parts of 1-acetyl-4-[2-(4-methoxyphenyl)-2-oxoethyl]piperidine and 50 parts of a hydrochloric acid solution 6 N is stirred and heated for 4 hours at 100° C. The reaction mixture is allowed to cool to room temperature. The precipitated product is filtered off and crystallized from 2-propanol, yielding 5.8 parts (59%) of 1-(4-methoxyphenyl)-2-(4-piperidinyl)ethanone hydrochloride; mp. 250.7° C.
Reaction SMILES: C([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19](O)([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)C)(C(C)C)C(C)C)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([O:65][Si:66]([CH:73]([CH3:75])[CH3:74])([CH:70]([CH3:72])[CH3:71])[CH:67]([CH3:69])[CH3:68])[CH2:5][C:4]1=[O:76])C.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH:73]([Si:66]([CH:67]([CH3:69])[CH3:68])([CH:70]([CH3:72])[CH3:71])[O:65][CH:6]1[CH2:5][C:4](=[O:76])[CH2:3][CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][CH:19]([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]1[CH3:64])([CH3:74])[CH3:75]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3OC(C(OC)CC(C)CC(C)=CCC(=O)CC(O[Si](C(C)C)(C(C)C)C(C)C)C2C)C(OC)CC3C)CCC1O
Yield: 92 %

Procedure:
17-Ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (8.98 g, 8.14 mmol) was slowly added to methanol (70 ml) containing p-toluenesulfonic acid monohydrate (0.70 g). The compound slowly dissolved and after 2 hr. TLC hexane/ethyl acetate (3:1) indicated no starting material was present. The reaction mixture was diluted to 250 ml with MeCl2 and washed with saturated aqueous NaHCO3 (250 ml). The organic layer was separated and the aqueous layer was extracted with additional MeCl2. The combined organic extracts were washed with brine and dried over magnesium sulfate. After evaporation in vacuo, the residue was chromatographed over SiO2 and eluted with MeCl2 /isopropanol (100:3) to yield 17-ethyl-1-hydroxy, 14-triisopropylsilyloxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (6.77 g, 87.9%). Mass Spec: C52H88NO12Si (948.37) FAB+Li:955 (M+Li), 721, 695, 676, 553, 266.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[C:24]([C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1)#[CH:25]>CCCCCCC.C(Cl)Cl>[C:26]1([C:24]#[C:25][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Reactant: C#CC1=CCCCC1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cn1nc(-c2ccccc2)cc1C#CC1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (110 mg, 84%); 1H NMR δ (CDCl3): 7.78 (d, J=8.09 Hz, 2H), 7.42-7.33 (t, J=8.11 Hz, 2H), 7.32 (m, 1H), 6.62 (s, 1H), 6.31-6.27 (m, 1H), 3.94 (s, 3H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 246.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:30]1[CH2:35][CH2:34][C@H:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37]2)[C@H:32]([CH2:45]O)[CH2:31]1)[CH3:29].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:28]([N:30]1[CH2:35][CH2:34][C@H:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37]2)[C@H:32]([CH2:45][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:31]1)[CH3:29]
Reactant: CCN1CC[C@H](N2CCc3ccccc32)[C@H](CO)C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCN1CC[C@H](N2CCc3ccccc32)[C@H](COc2ccc(F)cc2)C1
Reaction time: 8 h
Yield: 24.5 %

Procedure:
Under a nitrogen gas stream, 4-fluorophenol (168 mg) and triphenyiphosphine (420 mg) were added to a solution of cis-1-(1-ethyl-3-hydroxymethylpiperidin-4-yl)indoline (300 mg) in tetrahydrofuran (4 ml). After cooling the resultant mixture to −10° C., diethyl azodicarboxylate (278 mg) was gradually added dropwise thereinto. Then the resultant mixture was gradually warmed to room temperature and stirred at the same temperature overnight. After adding water (40 ml), the reaction mixture was extracted with ether (40 ml) for three times. The organic phase was washed successively with a saturated aqueous solution (40 ml) of sodium bicarbonate and a 1 N aqueous solution (40 ml) of sodium hydroxide, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia Chemical Ltd. NH-DM2035, hexane/ethyl acetate system) to give the title compound (100 mg) as a colorless oil (yield: 25%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH2:26])=[O:25])#[CH:16]>C(N(CC)CC)C.CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([O:10][C:8](=[O:9])[NH:7][C:5]1[CH:6]=[C:2]([C:16]#[C:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([NH2:26])=[O:25])[S:3][CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1csc(Br)c1
Reactant: C#Cc1ccccc1NC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1csc(C#Cc2ccccc2NC(N)=O)c1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a degassed solution of 2-bromo-4-(N-tert-butyloxycarbonylamino)thiophene (261 mg, 0.94 mmol, 1 eq), 1-(2-ethynylphenyl)urea (200 mg, 1.5 eq), and triphenylphosphine (6.2 mg, 0.025 eq) in anhydrous triethylamine (2 mL) and DMF (0.5 mL) was added bis(triphenylphosphine)palladium(II) dichloride (66 mg, 0.1 eq) and copper(I) iodide (18 mg, 0.1 eq). The mixture was stirred and heated at 80° C. for 30 minutes, then cooled to room temperature and diluted with ethyl acetate. It was washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (EtOAc-Hex from 1;100 to 1:1) to yield tert-butyl[5-({2-[(aminocarbonyl)amino]phenyl}ethynyl)-3-thienyl]carbamate as a yellow oil (194 mg) which was converted to a foam after dried in vacuo.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:3][NH:2][CH3:1])[CH2:10][CH2:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNC(=O)[C@H]1CC[C@H](OCCCCOCc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@H]1CC[C@H](OCCCCOCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.2 g (6.88 mmol) trans-4-(4-benzyloxy-butoxy)-cyclohexanecarboxylic acid methylamide dissolved in 10 ml of tetrahydrofuran were added slowly to a suspension of 0.261 g of lithium aluminium hydride in 10 ml of tetrahydrofuran. The reaction mixture was then stirred at 50° C. for 2 hours, cooled to 0° C., treated with 2 g of ice, stirred at room temperature for 30 minutes, diluted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give 2.05 g (97.4%) trans-[4-(4-benzyloxy-butoxy)-cyclohexylmethyl]-methyl-amine as light brown viscous oil, MS: 306 (MH+).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C.[CH3:28][C:29]1[N:33]([CH2:34][C:35]([N:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][CH:45]=[C:46]([C:48](O)=[O:49])[N:47]=3)[CH2:39][CH2:38]2)=[O:36])[N:32]=[C:31]([C:51]([F:54])([F:53])[F:52])[CH:30]=1>ClCCl.O>[CH3:28][C:29]1[N:33]([CH2:34][C:35]([N:37]2[CH2:38][CH2:39][N:40]([C:43]3[S:44][CH:45]=[C:46]([C:48]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:49])[N:47]=3)[CH2:41][CH2:42]2)=[O:36])[N:32]=[C:31]([C:51]([F:54])([F:52])[F:53])[CH:30]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)O)cs2)CC1
Reactant: OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Reaction time: 8 h

Procedure:
At room temperature, cyclohexanol (82 mg), dimethylaminopyridine (10 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (150 mg) are added to a solution of 2-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)-1,3-thiazole-4-carboxylic acid (XXXIV-1, 300 mg) in dichloromethane (5 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried with sodium sulphate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)-1,3-thiazole-4-carboxylate (45 mg, 12%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:20]2)=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][N:14]([CH3:13])[N:15]=3)[CH:20]=2)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3nn(C)cc3c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3nn(C)cc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((2-methyl-2H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 16).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccccc2n1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3ccc4ccccc4n3)c2cc1OC
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 9, 2-aminoquinoline was reacted with 4-chloro-6,7-dimethoxyquinazoline to give 6,7-dimethoxy-4-(2-quinolylamino)quinazoline in 56% yield, m.p. 215°-216° C.;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[Li+].[BH4-]>C1COCC1>[F:12][C:2]([F:1])([F:13])[C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1cccc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-trifluoromethyl-pyridine-2-carboxylic acid (500 mg, 3 mmol) in dry THF at 0° C., was added triethylamine (0.36 mL, 2.6 mmol) followed by ethyl chloroformate (0.25 mL, 2.6 mmol). After 30 min, LiBH4 (2 M in THF, 3.3 mL, 6.5 mmol) was added. After an additional 30 min, the ice bath was removed. After 1 h, the reaction was cooled to 0° C. and quenched with MeOH followed by 1N NaOH and EtOAc. The pH of the solution was adjusted to pH=5 with 1N HCl and the mixture extracted with EtOAc (2×). The combined organic fractions were dried to provide the title compound that was used without further purification. 1H NMR (CDCl3): 7.89 (dd, J=7.8, 7.8 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 4.85 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([N:31]=[N+:32]=[N-:33])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:31]([CH2:13]/[CH:12]=[CH:11]/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N+:32]=[N-:33]
Reactant: OC/C=C/C=C/CCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC/C=C/C=C/CCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2E,4E)-7-Phenylhepta-2,4-dien-1-ol (6.8 g) was dissolved in dry toluene (130 ml) and cooled in an ice-salt bath. Diphenyl phosphorazidate (7.83 ml) was added, followed by dropwise addition of DBU (6.53 ml) in dry toluene (15 ml). The mixture was stirred for 15 h while warming to room temperature. Solvents were evaporated and the residue was partitioned between diethyl ether and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography yielded a colorless liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:7]([OH:9])=O.[NH2:20][C:21](=[N:38]O)[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:37])[CH:23]=1>>[F:37][C:24]1[CH:23]=[C:22]([C:21]2[N:38]=[C:7]([C:6]3[CH:10]=[CH:11][C:12]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=3)[O:9][N:20]=2)[CH:36]=[CH:35][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Product: CCOC(=O)CCCOc1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(COC)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 58 (158 mg; 0.60 mmol) and Intermediate 66 (162.04 mg; 0.57 mmol), the crude mixture was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.30 (d, J=2.1 Hz, 1H), 8.07 (dd, J=8.2, 2.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.06 (t, J=8.5 Hz, 1H), 4.67-4.61 (m, 2H), 4.20-4.13 (m, 4H), 3.49 (s, 3H), 3.17 (br s, 1H), 3.06-3.03 (m, 1H), 2.65 (br s, 1H), 2.57 (t, J=7.3 Hz, 2H), 2.19 (quint, J=6.6 Hz, 2H), 1.86-1.70 (m, 4H), 1.51-1.48 (m, 2H), 1.27 (t, J=7.1 Hz, 3H), 0.90 (d, J=6.0 Hz, 3H). LC/MS (Method B): 512.4 (M+H)+. HPLC (Method A) Rt 4.62 min (Purity: 100.0%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:34][CH:33]([N:35]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:32]3)[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].O.NN>CCO.C(Cl)Cl>[NH2:35][CH:33]1[CH2:34][N:31]([C@H:28]2[CH2:29][CH2:30][C@H:25]([CH2:24][NH:23][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][C:19]([F:21])([F:22])[F:20])[N:6]=3)[CH2:26][CH2:27]2)[CH2:32]1
Reactant: O=C1c2ccccc2C(=O)N1C1CN(C2CCC(CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1

Procedure:
2-[1-(4-{[5-Nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-azetidin-3-yl]-isoindole-1,3-dione (92 mg, 0.15 mmol) was dissolved in EtOH-CH2Cl2 (3 mL, 2:1). With stirring, hydrazine monohydrate (11.3 mg, 0.23 mmol) was added and the reaction was stirred at 25° C. for 3 h. The volatiles were removed in vacuo and the crude residue was purified via flash chromatography (SiO2, 1:9:90-NH4OH:CH3OH:CH2Cl2) to afford 46 mg (62%) of the target compound, m/z 496.35 [M+1]+.