Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][CH:17]=O)[CH:13]=[CH:14][CH:15]=1.[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH2:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH:45][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:40])[F:39])[C:2]=2[Cl:1])[CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1
Reactant: O=CCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetaldehyde (76 mg, 0.13 mmol) and glycine methyl ester (34 mg, 0.27 mmol) in 1,2-dichloroethane (15 ml) was stirred as room temperature for 10 minutes, and sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added. Next two drops of glacial acetic acid was added. The reaction mixture was stirred at room temperature for 18 hour and then quenched with 0.01N aqueous HCl (15 ml) The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (3×). The organic layers were combined with the 1,2-dichloroethane solution and were washed with brine (1×), dried over sodium sulphate, filtered and concentrated in vacuo. Preparative HPLC (YMC 75×30 mm, 25 ml/min, 90-100% CH3CN) afforded title compound as an oil, 70 mg (81%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Reaction time: 20 h
Yield: 54 %

Procedure:
A solution of 2-amino-4-chlorobenzoic acid (10 g, 0.06 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in a 300 mL 3-necked flask fitted with a magnetic stirring bar and a constant additional funnel. Bromoacetyl bromide was added dropwise over a 2 h period while maintaining the internal temperature between 0°-2° C. After the addition was completed, the ice-water bath was removed, and then the reaction mixture was stirred 20 h. The reaction mixture was cooled in an ice-bath, water (300 mL) was slowly added, and then the white crystalline product which formed was filtered. Recrystallization from EtOAc/hexane gave 9.2 g (54%) of the title compound as a white solid: mp 156.4°-158° C.; 1H NMR (DMSO-d6) δ13.99 (s, 1H, NH), 11.72 (s, 1H, COOH), 8.54 (d, 1H, J=2.0), 8.00 (d, 1H, J=8.8), 7.27 (dd, 1H, J=2.4, J=6.4), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ168.60, 165.54, 141.12, 138.51, 133.88, 123.36, 119.23, 115.58, 30.54; MS (EI, m/z) 293 (M+).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=2)[CH:10]=[C:9]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:8]=1>>[CH:1]1([O:5][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=3)[CH:10]=[C:9]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Reactant: OC1CCC1
Product: COCCOc1cc2c(OC3CCC3)nc(Nc3cc(C)[nH]n3)cc2cc1OC

Procedure:
Similar procedure as described in example 400 was used, starting from cyclobutanol and [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-Cyclobutoxy-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 399(MH+).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18](=[NH:20])[NH2:19])=[N:10]1.C([N:28](CC)CC)C.O.NN>C(O)C>[F:25][C:6]([F:5])([C:21]([F:22])([F:23])[F:24])[CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18](=[NH:19])[NH:20][NH2:28])=[N:10]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Agent: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N=C(NN)c1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g (about 1.144 mmol) of the compound from Example 13A were dissolved in ml of ethanol, and 462 mg (4.574 mmol) of triethylamine and 71 mg (1.144 mmol) of hydrazine hydrate (80% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. This gave 689 mg (purity about 60%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[CH:28]=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:34])[C:30]=1[C:31]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][N:14]=[C:13]2[NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[F:1])=[O:32]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Nc1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12)c1c(F)cccc1Cl
Yield: 52.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-14, 60 mg, 0.18 mmol), 6-chloro-2-fluorobenzoic acid (48 mg, 0.27 mmol), oxalyl chloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) in CH2Cl2 (2 mL) to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.69 (s, 1H), 10.16 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.57 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.02 (d, J=5.7 Hz, 1H), 7.74-7.68 (m, 2H), 7.63-7.51 (m, 2H), 7.44-7.36 (m, 2H); MS (m/z): 479.30 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16]([OH:18])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[OH-].[NH4+].CC[N:31]=C=NCCCN(C)C>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16]([NH2:31])=[O:18])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1c(N2CCOC(CF)C2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1c(N2CCOC(CF)C2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylic acid (68.0 mg, 0.000164 mol), 33% ammonium hydroxide (33:67, ammonia:water, 0.1416 mL), EDCI (94.2 mg, 0.000491 mol) and 1-HOBT (66.4 mg, 0.000491 mol) in DCM (7 mL, 0.1 mol) was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with water, the organic layer was dried and purified by column chloromatography to afford 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxamide (38 mg, 56%). LCMS: (FA) ES+ 414, ES− 412; 1H NMR (400 MHz, d1-chloroform) δ: 7.59 (d, 1H), 7.42 (dd, 1H), 7.31 (d, 1H), 6.00 (s, 1H), 4.50 (dd, 2H), 4.12-4.08 (m, 2H), 4.00-3.78 (m, 4H), 3.36-3.25 (m, 1H), 3.22-3.15 (m, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH3:20])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: Cc1ccccc1N
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Cc1ccccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 2-methylaniline following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: FC(F)(F)C(O)=O.C(O)(=O)C.[BH4-].[Na+].[CH3:14][C:15]1[C:26]([CH3:27])=[C:25]2[C:18]([CH:19](O)[C:20]3([CH2:23][O:24]2)[CH2:22][CH2:21]3)=[CH:17][C:16]=1[OH:29]>ClCCl>[CH3:14][C:15]1[C:26]([CH3:27])=[C:25]2[C:18]([CH2:19][C:20]3([CH2:23][O:24]2)[CH2:21][CH2:22]3)=[CH:17][C:16]=1[OH:29]
Reactant: Cc1c(O)cc2c(c1C)OCC1(CC1)C2O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(O)cc2c(c1C)OCC1(CC1)C2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred ice-cold solution of trifluoroacetic acid (2 mL) and acetic acid (2 mL) was added sodium borohydride (30 mg). After stirring 10 min, a solution of 7,8-dimethyl-4H -spiro[chromene-3,1′-cyclopropane]-4,6-diol added (30 mg) in 20 mL of dichloromethane was added in one portion. Immediately thereafter, additional 20 mg of sodium borohydride was added to the solution, which was stirred for another 10 min. The mixture was partitioned with dichloromethane and water, and the organic layer was washed, dried and evaporated. The residue was purified by silica gel column eluting with 15% EtOAc in hexane to give 7,8-dimethyl-4H-spiro[chromene-3,1′-cyclopropan]-6-ol as a white solid (20 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 79.9 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (720 mg, 2.0 mmol), 4-(methanesulfonyl)phenylboronic acid (600 mg, 3.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (347 mg, 0.3 mmol) in dioxane (6 mL) was added 2 M sodium carbonate solution in water (4 mL, 8 mmol). The resulting mixture was subjected to microwave irradiation for 60 min at 110° C. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-methanesulfonyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (696 mg, 80%) as a white solid: LC/MS m/e calcd for C25H25NO4S (M+H)+: 436.55, observed: 436.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]([CH:19]([CH3:22])[CH2:20][NH2:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]1([CH2:29][C:30]#[N:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.CCOCC>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[O:12]([CH:19]([CH3:22])[CH2:20][NH:21][C:30](=[NH:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCc1ccccc1
Reactant: CC(CN)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(CNC(=N)Cc1ccccc1)Oc1ccccc1

Procedure:
A mixture of 2-phenoxypropylamine p-toluenesulphonate (3.7 g.) and phenylacetonitrile (1.5 g.) was stirred and heated, in an oil-bath, to 270° for 11/2 hours. The mixture was cooled and dissolved in the minimum amount of boiling ethanol, and the solution was poured into a mixture of water (75 ml.) and ether (75 ml.). The mixture was shaken and the aqueous layer was separated, washed once with ether, and evaporated to half-volume under reduced pressure. An oil separated and crystallised after a few days. The product was filtered and recrystallised from water to give N-(2-phenoxypropyl)phenylacetamidine p-toluenesulphonate, m.p. 121°-124°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:15])[CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:15])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CC(C)c1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CC(=O)O)c1ccccc1Br
Yield: 105.5 %

Procedure:
To a solution of 28.04 g of ethyl 3-(2-bromophenyl)-3-methylpropionate (109.1 mmole) in ethanol (200 ml) and water (100 ml) was added 12.2 g of potassium hydroxide (218.2 mmole), and the mixture was heated under reflux for 5 hours. After the mixture was left standing at room temperature, it was concentrated to a half of the volume by distillation and diluted again with dilute hydrochloric acid. Dichloromethane was then added, and an aqueous ammonium chloride solution was added before extraction. The organic layer was dried over magnesium sulfate, and the solvent was removed by distillation to give 27.97 g of 3-(2-bromophenyl)-3-methylpropionic acid (quantitatively).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(O)[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:5])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-:32].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:32][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCCCCCCCCCCBr
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1(O)C=CC(c2ccccc2)=CC1
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCBr)cc2)cc1
Yield: 72.6 %

Procedure:
An acetone solution of 90 m moles (21.8 g) of 4-hydroxybiphenyl-4-carboxylic acid ethyl ester obtained in Example 24, 0.15 mole (45.0 g) of 1,10-dibromodecane, and 0.4 mole (55.3 g) of potassium carbonate was refluxed for four hours. The reaction solution was filtered. The filtrate was concentrated, and then purified by column chromatography, to obtain 29.9 g of 4'-(10-bromodecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 72%)
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:11]=1)=[O:8])(=O)C.Cl.CCOC(C)=O>C1COCC1>[OH:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1)=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Oc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Oc1cccc(CO)c1)c1ccccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.3 %

Procedure:
To a solution of Compound 5 (9.4 g, 0.024 mol) in THF (120 ml) was added a solution of hydrochloric acid (HCl) (100 ml, 6 N HCl in water) at RT. The reaction mixture was stirred at RT for 2 days. Then, the reaction mixture was mixed with EtOAc (300 ml) and the resulting layers were separated. The organic layer was washed with aqueous saturated NaHCO3 (3×100 ml) and brine (1×100 ml). The aqueous layer was neutralized to pH 7 with aqueous saturated NaHCO3, and extracted with EtOAc (2×100 ml). These EtOAc extracts were combined and washed with brine (1×100 ml). Then, all the organic layers were combined and dried over anhydrous Na2SO4. The crude product obtained upon concentration was purified by column chromatography (elution solvent: 30% EtOAc in hexanes) to yield 5.0 g of Compound 6 in 87% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH:16]=[N:17][CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2ccc3c(c2)C2C=NCCC2O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.221 g, 0.53 mmol) was dissolved in CH2Cl2 (7 mL). Trifluoracetic acid (0.81 mL, 20 equiv.) was added, and the reaction mixture was stirred at rt under N2 for 2 h. The reaction mixture was cooled to −5° C. and 2N aqueous NaOH (8 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The water layer was extracted with CH2Cl2 (2×) and with 25:1 CH2Cl2:CH3OH (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.16 g, 98%). MS (ESI+) for C17H15Cl2NO m/z 320.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH2:30]1[C:32]2([CH2:37][CH2:36][NH+:35]([CH2:38][B-](F)(F)F)[CH2:34][CH2:33]2)[CH2:31]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:38][N:35]5[CH2:36][CH2:37][C:32]6([CH2:30][CH2:31]6)[CH2:33][CH2:34]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)C[NH+]1CCC2(CC1)CC2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCC4(CC3)CC4)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (6-azonia-spiro[2.5]octan-6-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: Br[CH:2](Br)[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].C([O-])(=O)C.[Na+].[Cl:15][C:16]1[C:21]([O:22][C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:20][C:19]([NH:29][NH2:30])=[C:18]([F:31])[CH:17]=1>O>[Cl:15][C:16]1[C:21]([O:22][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:28]=2)=[CH:20][C:19]([NH:29][N:30]=[CH:2][C:3](=[O:4])[C:5]([F:8])([F:7])[F:6])=[C:18]([F:31])[CH:17]=1
Reactant: NNc1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NNc1cc(Oc2ncccn2)c(Cl)cc1F)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1,1-Dibromo-3,3,3-trifluoroacetone (0.162 g) was added to a solution of sodium acetate (0.162 g) in water (0.5 ml) and the solution heated at 80° C. for 20 minutes. It was cooled to 0° C. and 4-chloro-2-fluoro-5-(pyrimidyloxy)-phenylhydrazine hydrachloride (0.15 g) was added. After stirring at room temperature for 2 hour the reaction mixture was processed to give 3,3,3-trifluoro-2-oxopropanal 4-chloro-2-fluoro-5-(pyrimidyloxy)-phenylhydrazone (0.122 g) mp=188-90° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].C([Li])CCC.[CH3:12][N:13]1[C:21]2[N:20]=[CH:19][N:18]([CH2:22][CH2:23][CH3:24])[C:17]=2[C:16](=[O:25])[N:15]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[C:14]1=[O:31].C(Cl)(Cl)Cl>CCCCCC.O1CCCC1>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]#[C:6][C:28]([OH:30])([CH3:29])[CH2:27][CH2:26][N:15]1[C:16](=[O:25])[C:17]2[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[N:20][C:21]=2[N:13]([CH3:12])[C:14]1=[O:31]
Reactant: C#CCN(C)C
Reactant: CCCn1cnc2c1c(=O)n(CCC(C)=O)c(=O)n2C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCn1cnc2c1c(=O)n(CCC(C)(O)C#CCN(C)C)c(=O)n2C

Procedure:
4.32 g (52 mmol) of N,N-dimethyl-2-propynylamine, 32.4 ml (52 mmol) of n-butyllithium as 1.6 M solution in n-hexane and 11.1 g (40 mmol) of 3-methyl-1-(3-oxobutyl)-7-propylxanthine were reacted in tetrahydrofuran and worked up in analogy to Example 1C2), but using chloroform in place of dichloromethane as extractant.
Reaction SMILES: [N:1]12[CH2:7][C:5]([C:8]([NH2:10])=[O:9])([CH2:6]1)[CH2:4][CH2:3][CH2:2]2.[C:11]1(=O)[O:15][CH:14]=[CH:13][O:12]1.[C:17](=[O:20])([O-:19])[O-].[K+].[K+]>>[C:11]([OH:15])(=[O:12])[C:17]([OH:19])=[O:20].[O:9]1[CH:14]=[CH:13][N:10]=[C:8]1[C:5]12[CH2:7][N:1]([CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=c1occo1
Reactant: NC(=O)C12CCCN(C1)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C(=O)O
Product: c1coc(C23CCCN(C2)C3)n1
Temperature: 120 °C

Procedure:
A well stirred mixture of 1-azabicyclo[3.1.1]hept-5-ylcarboxamide (D12, 640 mg, 0.0046 mole) and vinylene carbonate (600 mg, 0.0069 mole) in polyphosphoric acid (25 g) was heated at 120° C. for 1 h. The hot solution was then poured cautiously, with good stirring, into excess potassium carbonate solution. The aqueous mixture was saturated with potassium carbonate and extracted with ethyl acetate (1×100 ml), followed by chloroform (1×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo at room temperature. The residue was immediately chromatographed on basic alumina eluting initially with ethyl acetate, increasing to 15% methanol/ethyl acetate to give a colourless oil (60 mg). This was converted to its oxalate salt and recrystallised from methanol/ether to give the title compound (E4) as a white solid (65 mg, 6%) m.p. 165°-166° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4](SC)[N:3]=1.[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O.O>O1CCOCC1>[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([NH:32][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:6][N:5]=2)[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CSc1ncc(C(=O)OCc2ccccc2)c(C)n1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1C(=O)OCc1ccccc1
Yield: 34.8 %

Procedure:
A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate (6.0 g) and 1-benzyl-3-aminopyrrolidine (5.78 g) in dioxane (10 ml) was stirred at 130° C. for 15 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on allunima eluting with AcOEt-n-hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give benzyl 2-[(1-benzyl-3-pyrrolidinyl]amino)-4-methyl-5-pyrimidinecarboxylate (3.06 g).