Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH2:15]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:15][C:6]1[CH:5]=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][C:7]=1[C:2]#[N:3]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1N
Yield: 47 %

Procedure:
Heat a mixture of copper (I) cyanide (2.24 g, 25.00 mmol) and 2-bromo-4-trifluoromethyl-phenylamine (5.0 g, 20.83 mmol from Avocado) in 1-methyl-2-pyrrolidinone (20 ml) to 195° C. for four hours. Dilute the reaction mixture with 100 ml of ethyl acetate and wash the dark solution twice with 28% aqueous ammonium hydroxide, twice with saturated aqueous sodium chloride (brine) and twice with water. Collect the organic layer, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue via flash chromatography eluting with a step gradient starting with hexanes and going to 70% hexanes with 30% ethyl acetate to obtain 1.821 g (9.78 mmol, 47% yield) the title compound as a green amorphous solid: Mass Spectrum (m/e): 187(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]6[NH:32][C:33]([NH:35]C(=O)OC)=[N:34][C:29]6=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:42]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]6[NH:32][C:33]([NH2:35])=[N:34][C:29]6=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:42])=[CH:4][CH:3]=1
Reactant: CO
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ncncc3Cc3ccc(F)cc3)CCO4)nc2[nH]1
Agent: [K+]
Agent: [OH-]
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc5nc(N)[nH]c5n4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 100 °C
Yield: 46 %

Procedure:
To a solution of methyl [5-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3H-imidazo[4,5-b]pyridine-2-yl]carbamate (0.70 g, 0.129 mmol) in methanol (3 mL) was added 2 M aqueous potassium hydroxide (3 mL) and the mixture was heated at 100° C. for 1 hour. After cooling to room temperature the reaction mixture was concentrated and then diluted with water (5 mL) and the pH adjusted to 9 with 1 M hydrochloric acid. The resulting precipitate was collected by filtration, dissolved in a minimum of methanol and purified by preparative reverse phase HPLC to afford 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3H-imidazo[4,5-b]pyridin-2-amine (0.0283 g, 46% yield. 1H NMR (400 MHz, methanol-d4): 8.45 (s, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.17 (d, 1H), 7.11-7.06 (m, 3H), 7.01-6.96 (m, 3H), 4.55 (s, 2H), 4.30 (t, 2H), 4.00 (s, 2H), 3.89 (t, 2H), 2.22 (s, 3H); MS (EI) for C27H24FN7O: 482 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[O:11]2)[S:7][CH:8]=1)([O-:3])=[O:2].O.[NH2:21][NH2:22]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:11])[NH:22][N:21]=2)[S:7][CH:8]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: O=C1OC(=Cc2cc([N+](=O)[O-])cs2)c2ccccc21
Solvent: O
Product: O=c1[nH]nc(Cc2cc([N+](=O)[O-])cs2)c2ccccc12
Temperature: 90 °C

Procedure:
A suspension of 3-(4-nitro-thiophen-2-ylmethylene)-3H-isobenzofuran-1-one (26) (1.95 g, 5.17 mmol) in hydrazine monohydrate (0.6 mL, 12.0 mmol) was heated to 90° C. for 1 hour and then cooled to room temperature. The mixture was filtered and the filtered cake was washed with water (3×40 mL), hexane (2×40 mL) and dried in vacuo at 50° C. Two peaks in LC-MS analysis, (1.0 g, 61%) and required no further purification; m/z (LC-MS, ESP), RT=4.05 mins (M+H) 289, & RT=3.71 mins (M+H) 289.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][NH:8][C:9]1[S:10][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:12]([CH:14]=O)[N:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:7][NH:8][C:9]1[S:10][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:12]([CH:14]=[CH2:1])[N:13]=1
Reactant: CC(C)(C)[O-]
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=Cc1nc(NC)sc1-c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.1 %

Procedure:
Potassium tert-butoxide (1.46 g) was added to a solution of 2-methylamino-5-(4-pyridyl)-4-thiazolecarbaldehyde (1.9 g) and methyltriphenylphosphonium bromide (4.66 g) in dimethyl sulfoxide (87 ml) and the mixture was stirred for 5 hours at ambient temperature. The reaction mixture was poured into ice-water (300 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with a saturated aqueous solution of sodium chloride (100 ml) and dried over magnesium sulfate. Solvent was distilled off and the residue was subjected to column chromatography on silica gel (120 g) and eluted with a mixture of chloroform and methanol (40:1). The fractions containing the object compound were combined and concentrated until the volume was about 15 ml. The resultant white needles were collected by filtration and washed with cold ethyl acetate and dried under reduced pressure to give white needles of 2-methylamino-5-(4-pyridyl)-4-vinylthiazole (510 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:27])[CH3:26])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC1C=C2C(=CC=1)NC=C2)C1C=CC=CC=1>C(Cl)Cl.CO.[Pd]>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:25](=[O:27])[CH3:26])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Agent: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3-acetyl-5-benzyloxy-indol-1-yl)-acetic acid tert-butyl ester (MS: 380.0 [M+H]+; tR (HPLC conditions c): 5.72 min; prepared from 5-benzyloxy-1H-indole [1215-59-4] in a similar manner as described in Scheme A13 (step A and B)) (3.3 g, 8.70 mmol) in CH2Cl2/MeOH (80 mL) was added Pd/C (0.093 g, 0.870 mmol). The reaction mixture was stirred at RT for 5 h under H2 atmosphere. The reaction mixture was filtered over a pad of Celite and washed with CH2Cl2 and MeOH. Volatiles were evaporated, and the crude mixture was purified by flash chromatography on silica gel (gradient c-hexane/EtOAc 2:1 to 100% EtOAc). TLC, Rf (c-hexane/EtOAc 1:1)=0.35; MS: 312.0 [M+Na]+; tR (HPLC conditions c): 4.27 min.
Reaction SMILES: N1CCC[CH2:2]1.[CH2:6]([N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[CH3:25])[CH:15]([NH2:26])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[CH3:25])[CH:15]([NH:26][CH3:2])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(Cl)ccc1C1CN(Cc2ccccc2)CC1N
Reactant: C1CCNC1
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1C

Procedure:
In analogy to the procedure described for the synthesis of pyrrolidine intermediate VIII-1 (step c), the title compound [(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine was prepared from (3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-ylamine instead of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine and was obtained as a colorless oil. MS m/e: 315.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:25]=[O:26]>C1COCC1.CN1C(=O)N(C)CCC1>[OH:26][CH2:25][C:13]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)C1c2ccccc2Oc2ccccc21
Reactant: C=O
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CO)c2ccccc2Oc2ccccc21
Temperature: -50 °C
Yield: 68 %

Procedure:
A mixture of 1.5 g (5.9 mmol) of ethyl 9H-xanthene-9-carboxylate in 20 ml of THF and 1.6 ml of DMPU under an inert atmosphere is cooled to −50° C. 4 ml (6.4 mmol) of BuLi (1.6 M in hexane) are added dropwise to this medium with stirring, and the medium is then left stirring for 10 minutes at −40° C. After allowing the reaction medium to warm to 10° C., a flow of formaldehyde generated from 5.4 g (0.18 mol) of sublimed paraformaldehyde entrained by a stream of nitrogen is bubbled in. After stirring for 2 hours at room temperature, the suspension is dispersed in 50 ml of water. The reaction medium is then extracted twice with 100 ml of ether. The combined organic phases are dried over Na2SO4. After evaporation, the residual oil is chromatographed on silica. Eluent: CH2Cl2. 1.1 g of a yellow oil are obtained (yield: 68%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:4].Cl.[CH3:34][O:35][C:36](=[O:40])[CH2:37][NH:38][CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:32])[CH:10]=1
Reactant: CN(C)C(=O)c1cc(C=O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CNCC(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CNCCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-formylphenyl)amide (137 mg) and N-methylglycine methyl ester hydrochloride (45 mg) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (97 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1, v/v) to give the title compound (120 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])N.[CH:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>>[C:4]1([NH:1][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=CNc1ccccc1
Agent: NC(=O)[O-]
Product: O=C(Nc1ccccc1)Nc1ccccc1

Procedure:
In a separate run, the foregoing procedure is repeated except that the charge to the reactor additionally contains 4.0 grams of nitrobenzene. After 19 hours of reaction at a temperature of 180° C. and a CO pressure of 1000 psig, analysis of the reactor effluent from this second run shows methyl-N-phenyl carbamate to be formed in a yield of only 100%, based on cobalt charged, with a selectivity to a carbamate of only 50%, based on cobalt charged. The balance of products is found to comprise predominantly formanilide, with a minor quantity of diphenyl urea also being formed. There is also observed to be formed during the reaction a precipitate comprising Co(OH)2, resulting from the reaction of cobalt with water which is formed in the reaction mixture from --NO2 moieties in the system. The water therefore adversely combines with the cobalt carbonyl and removes the desired catalyst from the reaction.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].C(O[CH:10]1[NH:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=O)C>C1COCC1>[CH2:3]([S:5][C@@H:10]1[NH:13][C:12](=[O:14])[C@H:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[CH3:4]
Reactant: CC(=O)OC1NC(=O)C1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a 0° C. suspension of NaH (60% oil dispersion, 200 mg, 498 mmol) in THF (20 ml) was added ethanethiol (0.37 mL, 4.98 mmol). The resultant mixture was stirred for 10 min, cooled to -20° C., and compound 13 (1.9 g, 3.83 mmol) was added. The solution was stirred further for 30 min at room temperature and concentrated. The residue was partitioned between ethyl acetate and pH 7.0 aqueous buffer. The organic phase was washed with brine, dried (Na ), and concentrated. The residue was purified by silica gel chromatography (EtO2 ) to afford 718 mg (36%) of the title product.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.Br[CH2:27][CH2:28][CH2:29][C:30]#[N:31]>C(N(CC)CC)C>[C:30]([CH2:29][CH2:28][CH2:27][NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)#[N:31]
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Reactant: N#CCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCCCNc1cccc(/C=C/c2nc3ccccc3s2)c1
Yield: 40 %

Procedure:
To 50 ml of toluene were added 2.02 g of triethylamine and 5.04 g of 2-(trans-3-aminostyryl)benzothiazole at room temperature, and then 2.96 g of 4-bromobutyronitrile was added to carry out the reaction at 110° C. for 7 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. After evaporation of the solvent under reduced pressure, the residue was purified through silica gel column chromatography by use of ethyl acetate-ethyl ether-n-hexane (2:5:5) to give 2.55 g (yield 40%) of the title compound as colorless oily product.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].[CH:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=C>>[CH:3]1(/[CH:1]=[CH:2]\[O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:9])=[CH:13][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=CC1CCCCC1
Reactant: C=COc1ccc(OC)cc1
Product: COc1ccc(O/C=C\C2CCCCC2)cc1
Reaction time: 24 h
Yield: 75.3 %

Procedure:
Following the general procedure, vinylcyclohexane (20.0 mg, 0.182 mmol) was treated with p-methoxyphenyl vinyl ether (55.0 mg, 0.363 mmol) and 5 mol % of in situ-generated complex 1a (91.0 μL, 0.10 M, 9.08 μmol; final substrate concentration=2.0 M) and allowed to stir for 24 h. The unpurified product is >98% Z (as determined by 400 MHz 1H NMR analysis). Excess p-methoxyphenyl vinyl ether was removed by vacuum distillation (1.0 torr, 80° C.). The resulting oil was purified by neutral alumina chromatography (50:1 hexanes:Et2O) to afford 10d (31.8 mg, 0.137 mmol, 75.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 2925 (m), 2850 (m), 1664 (w), 1505 (s), 1465 (w), 1447 (w), 1392 (w), 1293 (w), 1244 (m), 1224 (s), 1180 (w), 1102 (w), 1040 (m); 1H NMR (400 MHz, CDCl3): δ 6.95-6:91 (2H, m), 6.86-6.82 (2H, m), 6.17 (1H, dd, J=6.4, 1.2 Hz), 4.63 (1H, d, J=9.2, 6.0 Hz), 3.78 Hz (3H, s), 2.65-2.54 (1H, m), 1.78-1.60 (5H, m), 1.39-1.06 (5H, m); 13C NMR (100 MHz, CDCl3): δ 155.2, 151.9, 139.8, 118.6, 117.5, 114.8, 55.9, 33.6, 33.5, 26.3, 26.1; HRMS (ESI+) [M+H]+ calcd for C15H21O2: 233.1542, found: 233.1542.
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1([CH3:22])[O:8][CH:7]2[CH2:9][C:10]([CH3:21])([CH3:20])[C:11]([CH2:15][Si](C)(C)C)(O)[C:12]([CH3:13])=[C:6]2[O:5]1.O>O1CCCC1>[CH3:3][C:4]1([CH3:22])[O:8][CH:7]2[CH2:9][C:10]([CH3:21])([CH3:20])[C:11](=[CH2:15])[C:12]([CH3:13])=[C:6]2[O:5]1
Reactant: CC1=C2OC(C)(C)OC2CC(C)(C)C1(O)C[Si](C)(C)C
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C(C)=C2OC(C)(C)OC2CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 171.8 %

Procedure:
23 ml of a 20% suspension of potassium hydride in oil (containing about 3.7 g/92 mmol KH) were pipetted into a 500 ml round flask provided with a magnetic stirrer and dropping funnel having a fitted argon bubble counter and washed three times with 10 ml of hexane each time. Then, 120 ml of tetrahydrofuran were added thereto and a solution of 25.0 g (83 mmol) of 2,2,4,6,6-pentamethyl-5,6,7,7a-tetrahydro-5-trimethylsilylmethyl-1,3-benzodioxol-5-ol in 220 ml of tetrahydrofuran was added dropwise thereto at room temperature and the mixture was stirred at room temperature for 30 minutes (GC control: educt no longer present). Then, the mixture was cooled to 0° C. and 50 ml of water were slowly added dropwise. An analogous working up to that in (i) gave 29.7 g of crude 2,2,4,6,6-pentamethyl-5,6,7,7a-tetrahydro-5-methylidene-1,3-benzodioxol as a yellowish oil. A distillation on a very short Vigreux column gave at a boiling temperature of 50° C./0.02 mbar (2 Pa) 15.6 g (90% yield) of pure product as a colorless oil. 1H-NMR (CDCl3, 250 MHz): inter alia 1.12 and 1.23 (2s, in each case 3H, C(6)—(CH3)2), 1.50 and 1.53 (2s, in each case 3H, C(2)(CH3)2), 1.73 (s, 3H, C(4)—CH3), 4.55 (m, 1H, CH—O—), 4.79 (d, J=6 Hz, ═CH2); IR (film): 1693, 1112 cm−1; mass spectrum: 208 (M+, 40), 107(100);
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45]>C(Cl)Cl>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([NH:4][CH2:3][C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:24][CH2:25][N:26]([C:36]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[O:46])[CH2:27][CH2:28]2)[CH2:19]1)=[O:1])=[O:16]
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a solution of N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (24 mg, 0.24 mmol) followed by 2-chlorobenzyl carbonochloridate (49 uL, 0.24 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then to the slurry was added NaHCO3 (sat. aq., 10 mL) and ethyl acetate (10 mL). The aqueous layer was separated and the organic layer was washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford 2-Chlorobenzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidine-1-carboxylate (35 mg, 38%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.43 (m, 2H), 1.56-1.64 (m, 1H), 1.69-1.74 (b, 2H), 2.14-2.35 (m, 3H), 2.56-2.68 (m, 2H), 2.86-2.88 (m, 3H), 4.01-4.06 (m, 4H), 4.40-4.42 (m, 1H), 5.16 (s, 2H), 6.50 (d, J=7.5 Hz, 2H), 7.18-7.22 (m, 4H), 7.30-7.34 (r, 2H), 7.50 (t, J=8.1 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 8.03 (s, 1H). MS m/z: 567 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[Li+]>O1CCCC1>[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
An oven-dried, three-necked, 1 L 24/40 round-bottom flask equipped with a mechanical stirrer, a septum and a nitrogen inlet was charged with a solution of 20.00 g (0.110 mol) of 4-chlorocinnamic acid in 400 mL of anhydrous tetrahydrofuran. The reaction mixture was purged with nitrogen and stirred at −20° C. and then 19.93 mL (0.143 mol) of triethylamine and 14.84 mL (0.120 mol) of pivaloyl chloride were added via syringe. The reaction mixture was stirred at −20° C. for 30 min, then at room temperature for 1.5 h. A separate, oven-dried, three-necked, 2 L 24/40 round-bottom flask was equipped with a mechanical stirrer, and a nitrogen inlet. The contents were purged with nitrogen gas and then charged with 16.243 g (0.092 mol) of (S)-(−)-4-benzyl-2-oxazolidinone, 4.274 g (0.101 mol) of finely powdered anhydrous lithium chloride, 400 mL of anhydrous tetrahydrofuran and 16.61 mL (0.119 mol) of triethylamine. The reaction flask was fitted with an oven-dried fritted vacuum filtration funnel in one of its necks, and the reaction mixture was stirred at −20° C. The mixed anhydride prepared in the first reaction flask was separated from precipitated triethylamine hydrochloride by rapid filtration into the second flask with the aid of a slight vacuum applied to the filtration funnel. The reaction mixture in the second flask was again purged with nitrogen, stirred for 30 min at −20° C., then allowed to warm to room temperature and stirred an additional 5 h. At this point the reaction mixture was filtered again and concentrated in vacuo. The crystalline residue was dissolved in methylene chloride, washed with 0.5 M hydrochloric acid, water, saturated aqueous sodium bicarbonate, brine, then dried (MgSO4), filtered and evaporated. The residue was purified by rapid filtration through a six inch bed of silica gel 60 eluted with methylene chloride. Evaporation of the purified fractions and drying in vacuo afforded 23.38 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([OH:24])[CH3:23]>Cl>[CH2:22]([O:24][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:23]
Reactant: CCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Product: CCOc1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 3.98 g (20.0 mmol) in ethanol 4 mL and concd HCl 3 mL was stirred at room temperature for 14 h. After removal of ethanol, the residue was dissolved in ethyl acetate, and the organic solution was washed with water, satd Na2CO3, and dried over anhydrous MgSO4. After removal of solvent under reduced pressure, the crude product was purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.91-7.94 (m, 1H), 7.54-7.61 (m, 2H), 7.25-7.29 (m, 2H), 7.12-7.16 (m, 1H), 6.90-6.94 (m, 1H), 4.29 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 3.60 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); LC-MS (ESI+; 310 ([M+H]+)).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:7][C:8]([Cl:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a 0° C. solution of cyclohexaneacetic acid (2.12 g, 14.9 mmol) in 30 mL of CH2Cl2 was added two drops of DMF followed by oxalyl chloride (1.3 mL, 14.9 mmol). The solution was warmed to r.t. and stirred overnight. The solvent was remove in vacuo to give 1.60 g of the title compound as a colourless liquid.