Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH2:10][O:9][C:8]1=[O:20].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:19][C:14]1[CH:13]=[C:12]([C@H:11]2[CH2:10][O:9][C:8](=[O:20])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: O=C1OC[C@H](c2ccc(F)c(F)c2)N1CCCCCCl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (4S)-3-(5-chloropentyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.32 (d, 1H, J=8.6 Hz), 7.26-7.21 (m, 2H), 7.20-7.12 (m, 2H), 7.06 (m, 1H), 6.97 (d, 1H, J=6.96 Hz), 4.76 (dd, 1H, J=6.3, 8.3 Hz), 4.62 (t, 1H, J=9.0 Hz), 4.06 (dd, 1H, J=6.4, 8.7 Hz), 3.46 (m, 1H), 3.0 (d, 2H, J=9.0 Hz), 2.77 (q, 1H, J=6.8 Hz), 2.50 (q, 2H, J=6.8 Hz), 2.31 (t, 2H, J=6.8 Hz), 2.01 (m, 4H), 1.81 (m, 4H), 1.48 (m, 4H), 1.26 (d, 6H, J=7.3 Hz); Anal. Calcd for C28H37F2N3O3+HCl+0.25CHCl3: C, 60.6; H, 6.65; N, 7.25. Found: C, 60.7; H, 6.91; N, 7.05; ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[CH:13]=[CH:12][C:11]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:3]1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.O1CCCC1>[CH:28]1([CH2:31][N:24]2[CH2:25][CH2:26][N:21]([C:11]3[CH:12]=[CH:13][C:14]([C:16]4[S:17][CH:18]=[CH:19][N:20]=4)=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:27])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:22][CH2:23]2)[CH2:30][CH2:29]1
Reactant: CC1(C)CC(c2cc(-c3nccs3)ccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CC(c2cc(-c3nccs3)ccc2N2CCN(CC3CC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine (15 mg, 0.039 mmol) produced in Example (99c), cyclopropanecarbaldehyde (0.006 mL, 0.080 mmol) and tetrahydrofuran (2 mL) were added sodium triacetoxyborohydride (21 mg, 0.099 mmol) and acetic acid (0.003 mL, 0.052 mmol) in that order, followed by stirring for 1 hour and 40 minutes at room temperature. Ethyl acetate, saturated aqueous solution of sodium hydrogencarbonate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was concentrated by blowing nitrogen. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated by blowing nitrogen, and then diethyl ether was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant diethyl ether solution was removed, and the obtained solid residue was dried by blowing nitrogen, to give 16 mg of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:22][C:23](=[O:28])[CH2:24][CH2:25][C:26]#[CH:27])[CH2:19][CH2:20][CH3:21]>CCN(CC)CC.[Cu]I>[CH2:18]([O:22][C:23](=[O:28])[CH2:24][CH2:25][C:26]#[C:27][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: C#CCCC(=O)OCCCC
Reactant: COc1ccc(CNc2cccc(Br)n2)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CCC#Cc1cccc(NCc2ccc(OC)cc2)n1
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a mixture of 14-2 (8.64 g, 29.48 mmol) and 14-4 (5.0 g, 32.4 mmol) in Et3N (50 mL) at 0° was added CuI (0.14 g, 0.74). The solution was purged with argon and [(C6H5)3P]2PdCl2 (0.52 g, 0.74 mmol) was added. After 1 h the cooling bath was removed and the solution was stirred for an additional 12 h. The solution was diluted with diethyl ether (250 mL) and washed with water (4×100 ml) followed by brine (100 mL). The ethereal layer was dried (Na2SO4), concentrated, and chromatographed (silica gel, 30% ethyl acetate/hexanes) to give 8.6 g of 14-5.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1ccc(F)cc1C(=O)Nc1ccccc1Cl
Yield: 57.7 %

Procedure:
Prepared according to Procedure A using 2-amino-5-fluorobenzoic acid (1.0 g, 6.45 mmol) and SOCl2 (1.2 mL, 16.1 mmol) in benzene (30 mL), followed by 2-chloroaniline (1.4 mL, 12.9 mmol) and CHCl3 (30 mL). The product was triturated from CH2Cl2 to provide 985 mg of a mustard-yellow solid (58%). 1H NMR (CDCl3) δ: 7.66 (dd, J=2.9, 8.7 Hz, 1H); 7.52-7.55 (m, 1H); 7.32-7.37 (m, 3H); 7.09 (dt, J=3.0, 8.5 Hz, 1H); 6.71 (dd, J=4.3, 8.7 Hz, 1H). MS (ES): m/z 305.0 (M+40).
Reaction SMILES: [H-].[Na+].O1[C:7]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.Cl[CH2:15][C:16]1C=C[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.Cl>CN(C)C=O.[Cl-].[Na+].O1CCCC1>[CH3:23][O:22][C:18]1[CH:19]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH:7]1[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]1
Reactant: COc1cccc(CCl)c1
Reactant: OC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(COC2CCC(=O)CC2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
4.4 g of 60% sodium hydride in mineral oil (0.11 mole) were stirred in 35 ml absolute dimethylformamide under a nitrogen atmosphere. 15.7 g (0.1 mole) 1,4-dioxaspiro[4.5]decan-8-ol were dissolved in 65 ml dimethylformamide. This solution was added drop-wise to the sodium hydride suspension. 16 ml 1-chloromethyl-3-methoxybenzene (0.11 mole), dissolved in 25 ml dimethylformamide, were then added. The mixture was stirred for 30 minutes at 60° C., poured on to ice, extracted with ether and dried over sodium sulphate. After evaporation of the solvent, 29 g of crude product were obtained. This was stirred for 1 hour with a mixture of 190 ml tetrahydrofuran and 50 ml of concentrated hydrochloric acid in order to cleave the acetal. The product was diluted with saturated sodium chloride solution, and the phases were separated, extracted with ether and dried. After removal of the solvent by distillation, compound (8) which was obtained was purified with diisopropyl ether via a silica gel column.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[C:5]=1[CH2:22][CH3:23].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1Cl.OP([O-])(O)=O.[K+]>CS(C)=O>[CH:18]1([CH2:17][O:16][C:9]2[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[C:13]3[C:8]=2[O:7][C:6](=[O:21])[C:5]([CH2:22][CH3:23])=[C:4]3[NH:3][C:30]2[C:29]([Cl:32])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:24])[CH2:19][CH2:20]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CCc1c(N)c2ccc(OC)c(OCC3CC3)c2oc1=O
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1c(Nc2c(Cl)cncc2Cl)c2ccc(OC)c(OCC3CC3)c2oc1=O
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (8 mg, 60%, 0.2 mmol) was added to a solution of 4-amino-8-(cyclopropylmethoxy)-3-ethyl-7-methoxy-2H-chromen-2-one (24 mg, 0.083 mmol) and DMSO (3 mL) at rt under N2. After 5 min. 3,4,5-trichloropyridine (19 mg, 0.1 mmol) was added, and the reaction was heated at 60° C. After 2 h, more 3,4,5-trichloropyridine (25 mg, 0.14 mmol) was added followed by more sodium hydride (15 mg, 60%, 0.38 mmol). After an additional 2 h at 60° C., the reaction was poured into 1M KH2PO4 (40 mL) and extracted with ethyl acetate (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (7:3→1:4; hexanes:ethyl acetate) to give 8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-3-ethyl-7-methoxy-2H-chromen-2-one: MS (ESI): 434.8.
Reaction SMILES: [O:1]1[C@@H:3]2[C@H:4](O)[C@@H:5]3[C@@H:14]([C@@:15]4([CH3:27])[CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][C@@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[C@@H:7]2[CH2:29][C@@H:8]2[C:9]1=[O:28].[Cl:31]CCl.ClC(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1>[Cl:31][C@@H:4]1[C@H:3]2[O:1][C@:2]32[C@:15]([CH3:27])([CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19]3)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:28])[C@H:8]2[CH2:29][C@@H:7]12
Reactant: ClCCl
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 169 g of 5,6β-epoxy-7β-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one in a mixture of respectively 340 ml of dichloromethane, tetrachloromethane, and pyridine is combined with 200 g of triphenylphosphine and stirred for 2 hours at room temperature. The reaction solution is washed with water, dried over sodium sulfate, and evaporated to dryness under vacuum. The residue is stirred up with 310 ml of ethanol and filtered. The filter cake is washed with 175 ml of ethanol and dried under vacuum, thus obtaining 139.2 g of 7α-chloro-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one. An analytical sample, recrystallized from acetone-hexane, has a melting point of 228° C. [α]D =-100° (chloroform).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20].C([BH3-])#N.[Na+]>CCO.CCOC(C)=O>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c(Br)cncc12
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Brc1cncc2c(NCc3ccccc3)cccc12
Temperature: 90 °C

Procedure:
Under argon, benzaldehyde (584 μl, 5.75 mmol) is added to a solution of 8-amino-4-bromoisoquinoline (Intermediate 23.2, 1.11 g, 5 mmol) in absolute EtOH (60 ml). The mixture is heated at 90° C. for 24 h. It is cooled to 0° C. and then sodium cyanoborohydride (NaBH3CN, 3.3 g, 50 mmol) is added in small portions. The stirring is maintained for 2 h at room temperature. The reaction mixture is diluted with AcOEt (600 ml) and is then washed with water. The organic phase is dried over Na2SO4 and then evaporated. The residue is purified on silica gel, eluting with an AcOEt/petroleum ether (1/4) mixture.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:16]([NH:20][CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[CH2:17][CH2:18][CH3:19].C(N(CC1C=CC(OCC(OCC)=O)=C(C)C=1)C1C(C)=C(C2C=CC(OC)=CC=2)N=CN=1)CCC>>[CH2:16]([N:20]([CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: Cc1ccc(-c2ncnc(Cl)c2C)cc1
Agent: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C)cc2)c1C

Procedure:
Prepared from 4-chloro-5-methyl-6-(4-methylphenyl)pyrimidine and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate using the procedure of Intermediate 67.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)[C:31]([F:45])=[CH:30][N:29]=1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]2[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52][C:51]=2[CH:59]=1>>[F:45][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)=[N:33][C:28]([NH:46][C:47]2[CH:48]=[CH:49][C:50]3[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52][C:51]=3[CH:59]=2)=[N:29][CH:30]=1
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC(C)C)cc4)n3)ccc2O1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yield 5-fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.87 (d, 1H, J=3.0 Hz), 7.47–7.42 (m, 3H), 7.12 (dd, 1H, J=2.4 and 8.4 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.80 (d, 1H, J=8.7 Hz), 6.63 (d, 1H, J=2.4 Hz), 5.21 (dd, 1H, J=6.3 and 10.5 Hz), 4.53 (2q, 1H, J=5.7 Hz), 3.80 (s, 3H), 3.52 (dd, 1H, J=10.5 and 15.9 Hz), 3.35 (dd, 1H, J=6.3 and 15.9 Hz), 1.34 (d, 6H, J=5.7 Hz); 19F NMR (CDCl3): −47664; LCMS: ret. time: 23.78 min.; purity: 95%; MS (m/e): 439 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:24][Si](CC)(CC)CC)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=O)[CH3:33].[NH4+].[Cl-].CCOCC>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:32][CH3:33])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([OH:24])([C:16]([F:18])([F:19])[F:17])[C:20]([F:21])([F:23])[F:22])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCN(Cc1ccccc1)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 200 mg (0.43 mmol) of trans benzyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine (example 3.1) in 2 mL of pyridine was treated with 0.05 mL of acetic acid anhydride (0.51 mmol), stirred overnight at RT and distributed between a saturated aqueous solution of NH4Cl and Et2O. After drying of the combined organic phases over Na2SO4 and evaporation of the solvent, the residue was dissolved in 3.5 mL of THF and treated with 0.86 mL of a 1M BH3-solution in THF. The mixture was stirred at RT for 2 hrs, and the solvent evaporated. The residue was redissolved in THF treated with an excess of TBAF and solution was stirred for 2 hrs. Evaporation of the solvent and chromatography on silica gel with hexane/EtOAc 4:1 gave 64 mg (39%) of trans 2-[4-(benzyl-ethyl-amino)-cyclohexyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol as a light yellow oil, MS: 384 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1([NH:15][CH:16]=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl.CC(O)C>[O:12]1[CH2:13][CH2:14][C:9]2([N:15]=[CH:16][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][CH2:1]2)[CH2:10][CH2:11]1
Reactant: O=CNC1(CCc2ccccc2)CCOCC1
Solvent: ClCCl
Solvent: CC(C)O
Product: C1=NC2(CCOCC2)CCc2ccccc21
Yield: 13.9 %

Procedure:
Formamide 20 (3.65 g, 15.7 mmol) from the previous experiment is cyclized according to general procedure C to give imine 22 (0.47 g, 14%) as a yellow oil after FC (10:1 CH2Cl2 /iPrOH). 1H NMR (CDCl3) 8.35(s,1) , 7.50-7.45(m,1) 7.40-7.20(m,3), 4.10-3.95(m,2), 3.85-3.70(m,2), 3.15-3.05(m,2), 2.00-1.95(m,2), 1.85-1.70(m,4); 13C NMR (CDCl3) 157.88, 141.77, 135.23, 132.61, 129.89, 129.66, 126.21, 64.02, 58.32, 38.71, 37.25, 30.13; MS(MW=215.3, CI/CH4, eE=120 eV) m/z 216 [(M+H+), base peak], 199, 189, 171, 143, 117, 100, 83.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[N:16][N:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9])([O-])=O.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([C:32]2[NH:23][C:22]3[CH:21]=[CH:20][C:6]([NH:7][C:8]([C:10]4[CH:11]=[CH:12][C:13]5[N:17]=[N:16][N:15]([CH3:18])[C:14]=5[CH:19]=4)=[O:9])=[CH:5][C:4]=3[N:1]=2)=[CH:30][CH:29]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cn1nnc2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc21
Product: CN(C)c1ccc(-c2nc3cc(NC(=O)c4ccc5nnn(C)c5c4)ccc3[nH]2)cc1

Procedure:
Compound 190 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(1-methyl-6-benzotriazolylcarbonyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.78 (s, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.16 (dd, J=1, 8.5 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 8.01 (d, J=8.5 Hz, 2H), 7.84 (dd, J=2, 9 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 6.96 (d, J=9 Hz, 2H), 4.39 (s, 3H), 3.10 (s, 6H).
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].CCN(C(C)C)C(C)C.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>C(Cl)Cl>[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH:57][C:41]([C:26]1[CH:27]=[C:28]2[C:33](=[C:24]([CH:22]([OH:21])[CH3:23])[CH:25]=1)[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])=[O:43]
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CN(C)CCN
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
TSTU (104 mg, 0.34 mmol) at 25° C., was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (110 mg, 0.34 mmol) and DIPEA (0.066 mL, 0.38 mmol) suspended in DCM (1 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 1.5 hrs. N1,N1-dimethylethane-1,2-diamine (0.038 mL, 0.34 mmol) was then added and the mixture stirred at 25° C. for 30 minutes. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 5% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness, the residue was triturated in diethyl ether, collected by filtration and dried to afford N-(2-(dimethylamino)ethyl)-8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 0.205 mmol, 59.6%) as a off-white solid. Mass Spectrum: M+H+ 390.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:20]=[O:21])[N:11]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1.CC(C)=[O:24].[OH-].[Na+]>O>[Br:7][C:8]1[CH:9]=[C:10]([C:20]([OH:24])=[O:21])[N:11]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1
Reactant: O=Cc1cc(Br)cn1-c1ncccc1Cl
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
An aqueous solution of 1.2 g of potassium permanganate in 10 ml of water was added dropwise to a mixture of 0.72 g of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde and 15 ml of acetone while the mixture was retained at 40° C. The mixture was then stirred at 60° C. for 8 hours. Precipitates were filtered off to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid. A deposited precipitate was collected by filtration to obtain 0.56 g of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid of the formula:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:8][CH:7]=1.S([O-])([O-])(=O)=O.[NH2:22][CH2:23][CH2:24][NH:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27].C([O-])([O-])=O.[K+].[K+]>CC(O)C>[OH:14][CH:12]([CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=1)[CH2:13][NH:22][CH2:23][CH2:24][NH:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: NCCNC(=O)N1CCOCC1
Reactant: COCCOc1ccc(OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COCCOc1ccc(OCC(O)CNCCNC(=O)N2CCOCC2)cc1

Procedure:
4 g of 3-(4-(2-methoxyethoxy)phenoxy)-1,2-epoxypropane, 5.8 g of the sulphate of N-2-aminoethyl-4-morpholinecarboxamide, and 5.8 g of K2CO3 were refluxed in 2-propanol for 2 days. The mixture was filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with H2O. The organic phase was dried over Na2SO4, filtered and evaporated. The product was recrystallized from ethyl acetate. Yield 2.3 g. Melting point 69° C. (base). The structure was determined using NMR and equivalent weight.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH2:17])[C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2]
Reactant: C=Cc1cccc(NC(=O)OCC)c1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Nc1cccc(CC)c1C(=O)O

Procedure:
2-Ethoxycarbonylamino-6-vinyl benzoic acid (500 mg, 2.13 mmol) and 10% Pd-C (50 mg) in 40 ml absolute ethanol was stirred for 16 hrs under 40 psi H2 pressure in a Parr bomb at room temperature. The reaction mixture was filtered through a cone of Celite and the catalyst on Celite was washed with 15 ml ethanol. The combined filtrate was evaporated to dryness. Trituration with ether gave crystalline 2-ethoxycarbonylamino-6-ethylbenzoic acid of Formula (I) in quantitative yield. M.p. 71.5°-74.0° C.; IR (KBr) νmax =1725, 1700 cm-1. Analysis, C12H15NO4 : theory, C 60.75; H 6.37; H 5.90; found, C 60.82; H 6.38; N 5.88.