Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[C:16]([CH3:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Br:14][C:15]1[C:16]([CH3:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Cc1c(Br)cccc1C=O
Product: Cc1c(Br)cccc1CN1CCN(c2cc(=O)[nH]cn2)CC1

Procedure:
6-[4-(3-Bromo-2-methyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromo-2-methylbenzaldehyde (which may be prepared as described in N. Subasinghe et al. WO 2003099805). 1H NMR (400 MHz, CDCl3) δ 2.45-2.50 (m, 7H), 3.48-3.54 (m, 6H), 5.36 (s, 1H), 6.97-7.01 (m, 1H), 7.16-7.21 (m, 1H), 7.47-7.49 (m, 1H), 7.82 (s, 1H), 11.95 (br s, 1H). Mass spectrum (ES) MH+=363.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CCCC)CCCC)CCC>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:45]([O:44][C:40](=[O:43])[CH:41]=[CH:42][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1)[CH3:46]
Reactant: C=CC(=O)OCC
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h

Procedure:
A solution of 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (2.6 g, Reference Example 7), tri-o-tolylphosphine (0.37 g), palladium (II) acetate, ethyl acrylate (1.6 mL) and tributylamine (8.01 mL) in dry dimethylformamide (25 mL), under argon, was heated at 155° C. for 3 hours then stood at room temperature overnight. The reaction mixture was evaporated and the resulting black oil was partitioned between ethyl acetate (200 mL) and hydrochloric acid (200 mL, 2M). The organic phase was washed with hydrochloric acid (200 mL, 2M), then with water (100 mL), then with brine (100 mL), then dried over magnesium sulfate and then evaporated. The residual yellow oil was subjected to flash chromatography on silica under gradient elution conditions with a mixture of ethyl acetate and pentane (from 3:97 to 10:90, v/v) to give the title compound. LC-MS: RT=4.05 minutes; no molecular ion observed.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][CH:6]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:5]1=[O:32])#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:33]1[C:1]([CH2:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:7][CH:6]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:5]2=[O:32])=[N:2][N:35]=[N:34]1
Reactant: N#CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)OCc1ccccc1
Yield: 59.9 %

Procedure:
A mixture of 150 mg of 1,3-dihydro-1-cyanomethyl-3-[(benzyloxycarbonyl)amino]-5-phenyl-2H-1,4-benzodiazepin-2-one, 124 mg of sodium azide, and 102 mg of ammonium chloride was heated in 3 ml of dry N,N-dimethylformamide at 110° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in water, acidified with 1N HCl solution, and extracted twice with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and concentrated to give 180 mg of crude product. Purification via preparative thick layer chromatography on 4 1.0 mm×20 cm×20 cm silica gel plates (90:10:1, chloroform-methanol-acetic acid elution) afforded 99 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[BH3-]C#N.[Na+].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13]>O>[CH2:12]([O:14][C:15]([CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C1Cc2ccccc2N1
Yield: 89.8 %

Procedure:
To cooled trifluoroacetic acid (40 mL) at 0° C., NaCNBH3 (1.57 g, 25 mmol) was added portionwise with stirring. The reaction mixture was stirred for 15 min, and to which indole-2-carboxylic acid ethyl ester (1.2 g, 6.35 mmol) was added slowly, then the mixture was stirred at rt for an hour. After the completion of the reaction, water (150 mL) was added to the mixture, and which was stirred for 5 hr. The reaction was extracted by CH2Cl2 (40 mL×3), then organic layer was washed with saturated aqueous solution of NaHCO3 (40 mL×2) and water (40 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give the desired compound (1.09 g, 90%).
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[O:20][CH3:21].O>ClCCl>[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][CH3:3])=[O:16])=[CH:13][C:12]=1[O:20][CH3:21]
Reactant: COc1cc(C(=O)Cl)ccc1I
Reactant: CCN(CC)CC
Agent: CN
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(I)c(OC)c1
Yield: 46 %

Procedure:
4-Iodo-3-methoxy-N-methylbenzamide. N,N-Dimethylformamide (0.1 mL) was added to a solution of 4-iodo-3-methoxybenzoic acid (2.0 g, 7.2 mmol) in sulfuryl dichloride (20 mL), and the mixture was heated to reflux for 2 h. The excess sulfuryl dichloride was removed under reduced pressure to give the crude product 4-iodo-3-methoxy-benzoyl chloride. To a solution of methyl amine (0.72 g, 10.8 mmol) and triethylamine (2.18 g, 21.6 mmol) in dichloromethane (20 mL) was added dropwise a solution of the above 4-iodo-3-methoxy-benzoyl chloride in dichloromethane (15 mL) at 0° C. After the reaction was completed, water was added, the organic layer was separated, dried over sodium sulfate evaporated to give the crude product, which was purified on silica gel column (eluting with 10-17% ethyl acetate in petroleum ether) to give 4-iodo-3-methoxy-N-methylbenzamide (0.92 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.92 (d, J=8.0 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.31 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1O)=[O:6])([CH3:3])[CH3:2].C(N(S(F)(F)[F:43])CC)C.O>ClCCl>[CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1[F:43])=[O:6])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1O
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1F
Reaction time: 2 h

Procedure:
A solution of 5-chloro-2-hydroxy-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide (100 mg, 0.18 mmol) in dichloromethane is cooled to 0° C., treated with diethylaminosulfurtrifluoride (29 mg, 1.8 mmol), stirred for 2 hours, and treated with water. Organic layer is separated, dried over sodium sulfate, filtered, and evaporated. Purification by chromatography using ethyl acetate/hexane as eluent gives 5-chloro-2-fluoro-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide as solid; LC/MS: 542/544 (M+1)+; m.p.: 98-99° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[CH:14][C:13]=12>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:18]([C:16]1[CH:15]=[CH:14][C:13]2=[N:9][O:10][N:11]=[C:12]2[CH:17]=1)=[O:19]
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: CNc1ccccc1
Product: CN(C(=O)c1ccc2nonc2c1)c1ccccc1

Procedure:
Prepared from N-methylaniline and [2,1,3]-benzoxadiazole-5-carbonylchloride using the procedure described for Example 7. N-Methyl-N-phenyl-[2,1,3]-benzoxadiazole-5-carboxamide was isolated as a yellow oil. LC-MS, MH+=254; 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H); 7.64 (d, 1H, J=9.6 Hz); 7.34 (d, 1H, J=9.6 Hz); 7.29-7.09 (m, 5H); 3.54 ppm (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([O:22][CH2:23][CH3:24])=[CH2:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]1([CH:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([O:11][CH:20]([O:22][CH2:23][CH3:24])[CH3:21])[CH:9]=[CH2:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=COCC
Reactant: C=CC(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(OC(C)OCC)C(NC(=O)OC(C)(C)C)c1ccccc1
Yield: 86.5 %

Procedure:
526 mg (2.0 mmol) of 1-phenyl-1-t-butoxycarbonylamino-2-hydroxybut-3-ene, syn form, 20 cm3 of dry methylene chloride, 1.9 cm3 (20.0 mmol) of distilled ethyl vinyl ether and 50.2 mg (0.2 mmol) of pyridinium p-toluenesulphonate (PPTS) are introduced successively into a 50 cm3 single-necked flask placed under an argon atmosphere and equipped with a magnetic stirring system. The resulting homogeneous reaction mixture is left to react for 4.5 hours at a temperature of about 20° C. When the reaction is complete, 1 drop of pyridine is added and the reaction mixture is then diluted in 60 cm3 of methylene chloride. The organic phase is washed twice with water and twice with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. After filtration, the solvents are driven off under reduced pressure on a rotary evaporator. The residue obtained is purified by passage over a column of silica gel using a hexane/ether mixture (8/2 by volume) as the eluent. 580 mg (1.73 mmol) of 1-phenyl-1-t-butoxycarbonylamino-2-(1-ethoxyethoxy)but-3-ene are obtained with a yield of 87% in the form of two epimers in a ratio of 55/45, said product having the following characteristics:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: ClCCN1CCCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=603.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-pyrrolidine hydrochloride.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:25][CH2:24][C:23](=O)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:25][CH2:24][C:23]3([O:4][CH2:1][CH2:2][O:3]3)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1
Reactant: OCCO
Reactant: O=C1CCN(c2nc(Cl)nc3c2CCC3c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Clc1nc2c(c(N3CCC4(C3)OCCO4)n1)CCC2c1ccccc1
Yield: 15.9 %

Procedure:
The mixture of ethylene glycol (46.9 μL, 0.841 mmol), 1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one (Intermediate Gn) (132 mg, 0.421 mmol) and 4-methylbenzenesulfonic acid, H2O (8.00 mg, 0.042 mmol) in Benzene (1169 μL) was heated at reflux for 24 h in a Dean-stark apparatus. The resulting mixture was concentrated and purified by Prep-HPLC (Column: PHENOMENEX LUNA C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 H2O/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 H2O/ACN. Flow rate: 40 ml/min, 30-100, 20 min) to get 7-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (24 mg, 0.067 mmol, 15.94% yield). LC-MS (M+H)+=358.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.31 (2H, t, J=7.63 Hz), 7.20-7.25 (1H, m), 7.15 (2H, d, J=7.63 Hz), 4.21 (1H, dd, J=9.16, 6.10 Hz), 4.01-4.06 (4H, m), 3.89-3.97 (2H, m), 3.77-3.84 (2H, m), 3.26 (1H, ddd, J=15.03, 8.62, 5.95 Hz), 3.13 (1H, ddd, J=14.95, 8.85, 5.80 Hz), 2.53-2.63 (1H, m), 2.17 (2H, t, J=7.17 Hz), 2.03-2.12 (1H, m).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1([C:27](=O)[C:26]2N(C)C=N[C:21]=2N(C)C1=O)C>O>[CH:26]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[NH2:2])([CH3:27])[CH3:21]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) and tyrosine (7 g) were dissolved in water (1 L). Caffeine (50 g) was added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c(Cl)c1

Procedure:
A solution of 3-chloro-4-methylbenzoic acid (5.0 g, 29 mmol), N-bromosuccinimide (5.7 g, 32 mmol), benzoyl peroxide (710 mg, 2.9 mmol) in CCl4 (300 mL) was heated at reflux for 2.5 h. The mixture was concentrated under reduced pressure and dissolved in MTBE. The organic mixture was washed with 1N NaOH (3×25 mL). The aqueous mixture was acidified with 1N HCl to pH 2 and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford 4-(bromomethyl)-3-chlorobenzoic acid.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:10]([O:28][C:5](=[N:6][CH:7]([CH3:9])[CH3:8])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: CC(C)N=C=NC(C)C
Product: CCCCCCCC/C=C\CCCCCCCCOC(=NC(C)C)NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
A mixture of N,N'-diisopropylcarbodiimide (12.6 g, 0.1 mole), oleyl alcohol (26.8 g, 0.1 mole) and cuprous chloride (60 mg) is stirred at room temperature for 4 hours. Infrared analysis shows the reaction to be virtually complete. The reaction mixture is placed on a column of alumina (454 g) and eluted with methylene chloride to give 36.2 g of O-oleyl-N,N'-diisopropylisourea. The product is identified by mass spectrometry (molecular ion at m/e 394), infrared spectroscopy (the C=N band at 1660 cm-1) and nuclear magnetic resonance in deuterated chloroform; resonances are given in δ relative to tetramethylsilane: 0.9-2.2 (mutiplet 37 protons); 2.9-3.8 (multiplet 3 protons); 4.0 (triplet, 2 protons) 5.3 (multiplet, 2 protons).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.C([O:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])(C)C.C[O-].[Na+].Cl>O.C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[C:15](=[O:14])[CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CC(C)OC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A mixture of 4-methylacetophenone (0.85 g), isopropyltrifluoroacetate (1.0 g) and toluene (2 ml) was added to a mixture of sodium methoxide (0.4 g) and toluene (2 ml) at 35-40° C. The reaction mixture was stirred at 75° C. for 4 hours. The reaction mixture was cooled to 25-30° C. Water (2 ml) and aqueous HCl (3 ml, 20%) were added and the reaction mixture was stirred at 25-30° C. for 30 minutes. The layers were separated. Aqueous layer was extracted with toluene (2×2 ml). The organic layers were combined and the solvent was removed by distillation at 55° C. under vacuum to obtain the title compound (Yield: 1.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Br:11]Br.O>CC(O)=O>[Br:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cc(O)c(O)c(Br)c1
Yield: 447 %

Procedure:
To a solution of 3,4-dihydroxy benzaldehyde (115.48 g, 12 mmol) in 500 ml AcOH was added bromine (6.1 ml, 118 mmol) drop-wise in 50 ml AcOH over 10 min. After 4 h the mixture was poured into cold H2O. The precipitate was filtered, washed with cold H2O and dried in vacuum to give 3-bromo-4,5-dihydroxy-benzaldehyde (11.64 g, 48%) as a grey solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13](Cl)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C@H:22]([NH2:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([NH:31][C@H:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH3:21])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COc1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
136 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and S-(−)-1-(4-methoxyphenyl)ethylamine in accordance with general method 5. MS (ES+): m/z=445 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:14])(=[O:4])=[O:3].CN.[CH2:17]([N:19](CC)CC)C>>[CH3:14][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[S:2](=[O:4])(=[O:3])[NH:19][CH3:17])[C:9]([OH:11])=[O:10]
Reactant: CCN(CC)CC
Reactant: Cc1cc(C(=O)O)ccc1S(=O)(=O)Cl
Agent: CN
Product: CNS(=O)(=O)c1ccc(C(=O)O)cc1C
Yield: 87.3 %

Procedure:
4-Chlorosulfonyl-3-methyl-benzoic acid (0.99 g, 4.2 mmol), methanamine (2.0 mL of 33% w/v, 21 mmol), and triethylamine (1.8 mL, 13 mmol) were stirred for 45 min at rt. The reaction mixture was evaporated and the resultant oil was partitioned between ethyl acetate and 1N HCl. The organics were separated and washed with another portion of 1N HCl and then brine. The organics were dried over sodium sulfate and evaporated to give 3-methyl-4-(methylsulfamoyl)benzoic acid (841 mg, 87%). ESI-MS m/z calc. 229.0, found 230.5 (M+1)+; Retention time: 0.64 minutes (3 min run).
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][C:8]([C:21]([O:23]C)=[O:22])=[CH:9][CH:10]=2)[N:5]=1>O.CO>[NH2:3][C:4]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[C:11]2[C:6](=[CH:7][C:8]([C:21]([OH:23])=[O:22])=[CH:9][CH:10]=2)[N:5]=1
Reactant: COC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reaction time: 5 h
Yield: 110.2 %

Procedure:
Lithium hydroxide (29 mg, 1.2 mmol) in water (1 mL) was added to a solution of methyl 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylate (180 mg, 0.60 mmol) in methanol (2 mL) at room temperature. The starting material was consumed after stirring for 5 h, and the reaction mixture was concentrated and dried on lyophilizer to obtain the crude product (190 mg) as an amorphous white solid. (quantitative yield). 1H NMR (300 MHz, DMSO): δ 2.22 (s, 3H), 2.48 (m, 4H), 3.49 (m, 4H), 6.23 (b, 2H), 7.55 (M, 2H), 7.75 (d, 1H); Analytic LCMS (M+H)+: m/z=288.1.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]=[S:18]>>[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]1[NH:5][CH2:4][CH2:3][S:18]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: [NH3+]CCCl
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine, which was reacted with 3-(chloromethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene according to Method D2a to give 2-(4-nitrophenylimino)-3-((6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl)methyl)-1,3-thiazolidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].Cl.[CH2:11]([C@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:11]([C@@H:18]1[NH:19][CH2:20][CH2:21][N:22]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCN[C@@H](Cc2ccccc2)C1
Reaction time: 3 h
Yield: 110.8 %

Procedure:
2-Thiophenesulfonyl chloride (2.6 g, 14 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a stirring solution of (2S)-2-benzylpiperazine hydrochloride (4.5 g, 18 mmol), Hünig's base, (16 mL, 90 mmol), and CH2Cl2 (90 mL) at room temperature. After 3 h, silica gel (29 g) was added to the reaction mixture and the volatiles were removed in vacuo. The residue was subjected to column chromatography (120 g of silica, 2% MeOH in CH2Cl2) to give (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine (5.0 g) as a pale yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][CH3:29]>>[F:23][C:24]1[CH:25]=[C:26]([CH2:27][N:28]([CH3:29])[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNCc1cccc(F)c1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1cccc(F)c1
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 3-fluoro-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.20 (3H, s), 2.71 (2H, t, J=6.2 Hz), 4.02 (1H, t, J=5.8 Hz), 4.16 (2H, t, J=6.2 Hz), 4.39 (1H, t, J=5.9 Hz), 6.93 (1H, d, J=9.8 Hz), 7.00 (2H, d, J=7.8 Hz), 7.25 (1H, m), 7.57 (1H, m), 7.74 (1H, s), 7.79 (1H, d, J=4.2 Hz), 8.30 (1H, s), 8.59 (1H, m). [M+H] Calc'd for C19H19FN4O2, 355. Found, 355.