Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:19]=[CH:18][C:17]2[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.C(NC(C)C)(C)C>C(Cl)(Cl)Cl>[Br:8][C:14]1[C:13]([OH:20])=[C:12]2[C:17]([CH:18]=[N:19][C:10]([Cl:9])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cccc2cnc(Cl)nc12
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Product: Oc1c(Br)ccc2cnc(Cl)nc12
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Solid NBS (1.09 g, 6.11 mmole) was added to a stirred solution of 2-chloroquinazolin-8-ol (1.10 g, 6.11 mmole) and diisopropyl amine (2.2 mL, 15.30 mmole) in CHCl3 (60 mL) at −5° C. under argon. After stirring at −5 to 0° C. for 1 hour, LCMS showed that the reaction was complete. The reaction was evaporated to a residue which was dissolved in DMSO (5 mL) and purified by prep. HPLC. The pure product was obtained as a white solid in 51% yield (800 mg, 3.08 mmole).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([CH3:32])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:23]([C:17]1[CH:16]=[C:15]2[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:32])([CH3:33])[C:6]([OH:34])=[O:5])=[O:11])[N:13]=[C:14]2[C:30]#[N:31])=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 64.4 %

Procedure:
A mixture of 3-[(7-Benzyl-1-cyano-4-hydroxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid tert-butyl ester (22 mg, 0.05 mmole) in a mixture of trifluoroacetic acid (3 ml) and dichloromethane (1 ml) was stirred room temperature for 80 minutes before it was concentrated to give the title compound as a white solid (13 mg). LC-MS ESI−: 402 (M−1)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O.C(OCC)C.O>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[CH3:13]
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)cc(Br)c1
Temperature: 90 °C
Yield: 94 %

Procedure:
Sulphuric acid (10 drops) was added to 3-bromo-5-methylbenzoic acid (1.18 g, 5.49 mmol) in ethanol (20 ml) and refluxed at 90° C. for 20 hours. After cooling, the mixture was diluted with diethyl ether/water and the organic phase washed with sodium hydrogen bicarbonate (saturated solution), dried (magnesium sulphate) and evaporated to dryness to give the title compound as a pale yellow oil (1.249 g, 94%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].Cl.[NH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>C(Cl)Cl>[CH2:14]([O:13][C:11]([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:12])[CH:15]=[CH2:16]
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc([N+](=O)[O-])c1

Procedure:
Diisopropylethylamine (66 ml) and allyl chloroformate (22 ml) in 150 ml of methylene chloride were added at 0° C. to a solution of ethyl 3-amino-3-(3-nitrophenyl)-propionate hydrochloride from II.1b (47 g) in 350 ml of methylene chloride. After a reaction time of 30 min, HCl (1N, 100 ml) was added. The organic phase was separated off, washed with water, dried over MgSO4 and concentrated. A white solid was obtained (yield: 56.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 2 mL of dichloromethane was added methanesulfonyl chloride (0.007 mL, 0.091 mmol, 2 eq.) and triethylamine (0.02 mL, 0.137 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 12 mg (51%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81-2.18 (m, 4 H) 2.77-2.94 (m, 3 H) 3.07-3.29 (m, 2 H) 3.42 (br. s., 1 H) 3.82 (d, J=9.89 Hz, 1 H) 4.68 (br. s., 1 H) 6.13 (br. s., 1 H) 7.12-7.65 (m, 8 H) 8.48 (s, 1 H), [M+H]+ 517.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15]Br)[CH:5]=1.CC([O-])=[O:20].[K+].CO.C[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][OH:20])[CH:5]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cccc(-c2ncsc2CBr)c1
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cccc(-c2ncsc2CO)c1
Reaction time: 0.5 h

Procedure:
3-(5-Bromomethyl-thiazol-4-yl)-benzoic acid methyl ester was stirred in DMF (10 mL) together with KOAc (1.52 g) at 20° C. for 30 min. MeOH (20 mL) and NaOMe (0.84 g) were added and stirring was continued at 50° C. for 30 min. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt/hexane (1:2) as eluent to give 3-(5-hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1.43 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:23]([F:27])([F:26])[CH:24]=[CH2:25].O>CN(C)C=O>[F:26][C:23]([F:27])=[CH:24][CH2:25][O:14][C:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:15]
Reactant: C=CC(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCC=C(F)F)C1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of pyrrolidine-1,3-dicarboxylic acid-1-tert-butyl ester (3.40 g) in N,N-dimethylformamide (34 ml) were added potassium carbonate (4.37 g) and 3-bromo-3,3-difluoropropene (1.93 ml), and the mixture was stirred at 60° C. for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the titled compound (3.73 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].I[CH:30]([CH3:32])[CH3:31]>O>[NH2:1][C:2]1[N:3]([CH:30]([CH3:32])[CH3:31])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C(C)C)c(=O)c23)c(C)c1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (156 mg, 0.55 mmol) and N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of 2-iodopropane (102 mg, 0.60 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 3 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 88 mg (49%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:3]=1[C:16]#[N:17].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:17][C:16]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][C:4]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cccc(-c2cccc(N)c2C#N)c1
Product: CCOC(=O)c1c(C)nc2cccc(-c3cccc(OC)c3)c2c1N

Procedure:
Prepared as in Example 2a from 3-amino-3′-methoxy-[1,1′-biphenyl]-2-carbonitrile (Example 114b) and ethyl 3-oxobutanoate as a pale yellow solid (55%). MS 337 (MH+).
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:15]=1[C:16]([NH:18][CH3:19])=[O:17]>>[NH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:14]([F:13])[C:15]=1[C:16]([NH:18][CH3:19])=[O:17]
Reactant: CNC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: CNC(=O)c1cc(F)ccc1N
Product: CNC(=O)c1c(N)cccc1F

Procedure:
The title compound was prepared according to the procedure for Compound 102A (2-Amino-5-fluoro-N-methylbenzamide) using 2-fluoro-N-methyl-6-nitrobenzamide (Compound 155B). 1H NMR (CDCl3, 400 MHz): δ=2.99 (dd, J=4.80, 1.26 Hz, 3H), 6.35 (ddd, J=12.88, 8.08, 1.01 Hz, 1H), 6.44-6.49 (m, 1H), 7.09 (td, J=8.21, 6.57 Hz, 1H). MS (ES+): m/z 169.08 [MH+] (TOF, polar).
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NC(C4SC(C5C=CC=CC=5)=CN=4)=O)=CC=3)=CC=2)C1=O)C(OC)=O.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59][CH3:60])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[N:44][CH:45]=1.[C:64]1([C:70]2[O:74][C:73]([C:75](OCC)=[O:76])=[N:72][CH:71]=2)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[CH3:62][CH:61]([CH3:63])[C@H:56]([N:51]1[CH2:50][C:49]2[C:53](=[CH:54][C:46]([C:43]3[CH:42]=[CH:41][C:40]([NH:39][C:75]([C:73]4[O:74][C:70]([C:64]5[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=5)=[CH:71][N:72]=4)=[O:76])=[CH:45][N:44]=3)=[CH:47][CH:48]=2)[C:52]1=[O:55])[C:57]([O:59][CH3:60])=[O:58]
Reactant: CCOC(=O)c1ncc(-c2ccccc2)o1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cn3)cc2C1=O
Yield: 83 %

Procedure:
The compound of example 634 was prepared analogous to the compound of example 611 by reaction of compound of example 392 with ethyl 5-phenyloxazole-2-carboxylate.
Reaction SMILES: C(OC(C)(C)C)(=O)C=C.[CH3:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=O)=[CH:12]1.[CH3:22][N:23]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH2:20][NH:23][CH3:22])=[CH:12]1
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: Cn1cc(C=O)c2cccnc21
Agent: C=CC(=O)OC(C)(C)C
Product: CNCc1cn(C)c2ncccc12
Yield: 45 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:26])([CH3:25])[C:21](OC)=[O:22])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[CH:27]=1)(=[O:3])[NH2:2].OC(C)(C#C)C(OC)=O.BrC1C(F)=CC2OCC[N:44]3C=C(C(N)=O)N=C3C=2C=1.N>CO>[NH2:44][C:21](=[O:22])[C:20]([OH:26])([CH3:25])[C:19]#[C:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[O:10][CH2:9][CH2:8][N:7]3[CH:27]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Agent: C#CC(C)(O)C(=O)OC
Agent: N
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 15 %

Procedure:
similar to General Procedure M, A solution of methyl 4-(2-carbamoyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)-2-hydroxy-2-methylbut-3-ynoate (300 mg, 0.80 mmol, 1.00 equiv) (prepared by reaction of methyl 2-hydroxy-2-methylbut-3-ynoate and 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide in methanol saturated with ammonia (40 mL) was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was washed with 3×10 mL of methanol and 2×5 mL of CH3CN. The solid was dried in an oven under reduced pressure. This resulted in 43 mg (15%) of the title compound as a brown solid.
Reaction SMILES: [C:1]([C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.O>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(=O)c2ccccc2)CC1
Solvent: CO
Solvent: O
Product: CCOC(=O)C1(C(O)c2ccccc2)CC1
Temperature: 70 °C
Yield: 694.6 %

Procedure:
(S)-tBuBisP*-RuBr2 (25 mg) was placed in a reaction vessel and deaerated. After substitution with argon, a mixture of ethyl 1-benzoylcyclopropanecarboxylate (3.3 g, 1.0 mmol) and methanol-water (10/1) (33 ml) was added. The mixture was stirred at 70° C. and hydrogen pressure (6 kg/cm2) for 24 h, after which the reaction mixture was concentrated. This was concentrated to dryness, diluted with ethyl acetate, washed with water and purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (1.53 g, 46.3%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 85%.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:9][C:10](S(C)(=O)=O)=[N:11][C:12]=1[Cl:13])=[O:6])[CH:2]=[CH2:3].[C-:34]#[N:35].[Na+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:4][C:5]([C:7]1[C:8]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:9][C:10]([C:34]#[N:35])=[N:11][C:12]=1[Cl:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(Cl)nc(S(C)(=O)=O)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)c1c(Cl)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic procedure as described in Ref. Example 2, a solution of 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methanesulfonylpyrimidine-5-carboxylic acid allyl ester (1.8 mmol) in CH2Cl2 (5 mL) is treated with a solution of NaCN (2.2 mmol) and tetra-n-butylammonium bromide (0.10 mmol) in water (2 mL) for 0.5 h. After usual work-up, the crude material is purified by silica gel chromatography to give 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-6-chloro-2-cyanopyrimidine-5-carboxylic acid allyl ester as colorless oil; 1H-NMR (CDCl3), δ: 1.12-1.73 (9H, m), 1.48 (9H, s), 2.68 (2H, brt), 4.05-4.09 (2H, m), 4.55 (2H, t), 4.87 (2H, dt), 5.33-5.37 (1H, m), 5.41-5.47 (1H, m), 5.98 (1H, ddt).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6]C1C=C(B(O)O)C=CC=1.[NH2:16][C:17]1[CH:18]=[C:19]([B:23]([OH:25])[OH:24])[CH:20]=[CH:21][CH:22]=1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.Cl>N1C=CC=CC=1.O>[C:26]([OH:31])(=[O:32])[CH2:27][CH2:28][C:29]([NH2:6])=[O:30].[NH2:16][C:17]1[CH:18]=[C:19]([B:23]([OH:25])[OH:24])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: Nc1cccc(B(O)O)c1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Synthesis of this material was accomplished using a modification of the procedure in Weith, et al. Biochemistry 9:4396-4401 (1970). 3-Amino-phenylboronic acid hemisulfate (100 g, 0.535 moles) was suspended in anhydrous pyridine (240 mL). The mixture was stirred magnetically and chilled in an ice/water bath under an atmosphere of dry nitrogen. Succinic anhydride (56.5 g, 0.565 moles) was added to the flask, and the reaction mixture was allowed to warm to room temperature. After stirring overnight (at least 12 hours), all solids had dissolved. The majority of the pyridine was removed on a rotary evaporator (bath temperature ≤55° C.) to give a viscous, amber-colored syrup. The syrup was co-evaporated with water (100 mL), and the residue was then dissolved in water (700 mL). The amber solution was chilled in an ice-water bath, and concentrated hydrochloric acid (30-50 mL) was added slowly to yield a final pH of 1 (pH paper). During this addition, a white solid precipitated. The suspension was chilled for 1 hour at 4° C. The solid was filtered and washed with cold water (100 mL). The solid was then crystallized from hot water, and dried in vacuo over KOH pellets. Yield: 100 g (80%); m.p. 171°-172° C. (open capillary, uncorrected). 1H NMR (300 MHz, DMSO-d6): δ 12.07 (broad singlet, 1H, CO2H), 9.83 (singlet, 1H, ArNHCOR), 7.95 (singlet, 2H, BOH), 7.67 (singlet, 1H, ArH), 7.65 (doublet, J=7.9 Hz, 1H, ArH), 7.41 (doublet, J=7.0 Hz, 1H, ArH), 7.20 (apparent triplet, J=7.8 Hz, 1H, ArH), 2.60-2.40 (multiplet, 4H, COCH2). 13C NMR (75.5 MHz, DMSO-d6) δ 174.2, 170.2, 138.7, 129.0, 127.8, 125.2, 121.2, 31.0, 28.9. HPLC: Retention time of product, 8.6±0.1 minutes using an Applied Biosystems/Brownlee Aquapore Butyl 2.1×220 mm cartridge, and a mixed gradient elution as follows: A, 0.1M triethylammonium acetate, pH 6.5; B, methanol at a flow rate of 0.5 mL/minute beginning with 100% A/0% B, for 5 minutes, then to 0% A/100% B over 30 minutes at ambient temperature. Detection was carried out using a diode array detector: 260 nm, 280 nm, 300 nm. The sample amount was 5 mg/mL in methanol.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=O)[CH:3]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=[N:13][OH:14])[CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(Br)sc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1sc(Br)cc1C=NO

Procedure:
5-Bromo-2-nitrothiophene-3-carbaldehyde (22.5 g, 95 mmol), hydroxylamine hydrochloride (6.96 g, 100 mmol) and sodium acetate (8.21 g, 100 mmol) were stirred in ethanol (225 mL) at room temperature overnight. The solvent was removed in vacuo, saturated NaHCO3 was added and the mixture extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:25])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[OH:24])[C@H:9]([CH3:26])[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31][O:32][C:33](=[O:36])[CH2:34]Br>O1CCCC1>[CH3:31][O:32][C:33](=[O:36])[CH2:34][O:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][C:14]([N:10]1[CH2:11][C@H:12]([CH3:13])[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=2)[CH2:8][C@H:9]1[CH3:26])=[O:25]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)ccc1CCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Reaction time: 0.08 h
Yield: 103.8 %

Procedure:
To a solution of 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-(2-hydroxy-4-methyl-phenyl)-propan-1-one, (0.15 g, 0.38 mmol) in tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (0.023 g, 0.57 mmol). The reaction was stirred for 5 minutes, then bromoacetic acid methyl ester (0.043 mL, 0.45 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was quenched by the addition of water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.18 g).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[O-2].[Mg+2].C1COCC1>C(OCC)C>[CH3:12][C:6]([CH3:13])([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:5][CH:4]=[CH:3][CH2:2][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)CC(C)(C)CC=CCCl
Reactant: NCCN1CCNCC1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)CC(C)(C)CC=CCNCCN1CCNCC1

Procedure:
In a similar manner to Example 4, 10 g (4.95 mmol) of 1-chloro-5,5,7,7-tetramethyl-2-octene, 64 g (495 mmol) of 1-(2-aminoethyl)piperazine, 10 g (248 mmol) of magnesium oxide and 30 ml of THF are refluxed for 4 h. The mixture is diluted with 300 ml of diethyl ether and extracted once each with 5% strength aqueous NaOH and water, concentrated and dried at 40° C./1 mbar. Yield: quantitative.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2=[O:12].[C:13](Cl)([Cl:15])=[O:14]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:13]([Cl:15])=[O:14])[CH2:7][CH2:6][C:5]2=[O:12]
Reactant: O=C1CCNc2ccc(Br)cc21
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)Cl)c2ccc(Br)cc21
Reaction time: 2.5 h

Procedure:
45.2 Parts of 6-bromo-4-oxo-1,2,3,4-tetrahydroquinoline and 200 parts of dioxane were mixed, and 39.4 parts of phosgene was introduced to the stirred mixture while the temperature was maintained at 20°-25° C. over about 30 minutes. After the introduction, the reaction was effected at 40°-45° C. for 2.5 hours, and thereafter the mixture was treated as in Example 37 (a) to obtain 55.9 parts of 6-bromo-4-oxo-1-chloroformyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([N+:22]([O-])=O)[CH:5]=1.[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([NH2:22])[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1

Procedure:
45 g of 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid methyl ester are suspended in 150 ml of ethyl acetate and hydrogenated for 5 hours with Raney nickel at 50° C and a hydrogen pressure of 100 atmospheres gauge. After cooling, the Raney nickel is separated and the solution is concentrated to dryness. The 3-amino-4-(4'-methylphenoxy)-4-sulphamoylbenzoic acid methyl ester is recrystallised from methanol/H2O. Crystals melting at 183°-185° C.