Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1.B(Br)(Br)[Br:33].COC>ClCCl>[Br:33][CH2:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: BrB(Br)Br
Reactant: COCc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: COC
Solvent: ClCCl
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(CBr)c1)C(F)(F)F
Temperature: -50 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
EX-51 4D) The 3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol from EX-514C (1 g, 2.2 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to −50° C. and a 1 M solution of BBr3 in dichloromethane (2.3 mL, 2.3 mmol) was added. The solution was stirred at −50° C. for 1 hour and warmed to room temperature over 1 hour, at which time HPLC analysis indicated that no methyl ether starting material remained. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted in dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 0.65 g (59%) of the desired 3-[[3-(bromomethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C19H18BrF7NO2: 504.0409 [M+H]+, found: 504.0361. 1H NMR (CDCl3) δ3.3 (s, 1H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.4 (s, 2H), 4.8 (m, 2H), 5.9 (tt, 1H), 6.7 (d, 1H), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 4H), 7.4 (t, 1H).
Reaction SMILES: C1(S(C2C=CC=CC=2N[N:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])(=O)=O)C=CC=CC=1.[C:23]1([S:29]([C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[NH2:34])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(#N)CC#N.O.[NH2:45][NH2:46]>>[C:23]1([S:29]([C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[NH:34][N:17]=[C:18]2[C:19]([NH2:20])=[N:46][N:45]=[C:21]2[NH2:22])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccccc1S(=O)(=O)c1ccccc1
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccccc1S(=O)(=O)c1ccccc1

Procedure:
4-[(2-benzenesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 94 mg (0.5 mmol) of 2-[(2-benzenesulfonylphenyl)hydrazono]malononitrile, which was derived from 2-(phenylsulfonyl)aniline (233 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 20 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 68 mg (20%) of the compound as an orange coloured solid.
Reaction SMILES: [N:1]#[C:2][NH2:3].C(OC(=O)[N:10]([CH2:23][CH3:24])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)(C)(C)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=[O:29]>>[NH2:1][C:2]1[N:3]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:10][CH2:23][CH3:24])=[CH:19][CH:18]=2)[S:22][C:27]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=[O:29]
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: N#CN
Reactant: CCN(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Product: CCNCCOc1ccc(Nc2nc(N)c(C(=O)c3cccc(OC)c3)s2)cc1

Procedure:
This compound was prepared from cyanamide, ethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester of Example 129D and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) following the procedure of Example 123. The protecting group was removed with 50% trifluoroacetic acid in dichloromethane, evaporated to a gum, taken into ethyl acetate, treated with 0.01N aqueous sodium hydroxide for 15 minutes and then washed with water. The ethyl acetate was dried (Na2SO4) and concentrated to a semi-solid which was triturated with ether to yield solid [4-amino-2-[4-(2-ethylamino-ethoxy)-phenylamino]-thiazol-5-yl]-(3-methoxy-phenyl)-methanone. Mass spectrum (ES) MH+=413.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([NH2:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:15]([NH:23][C:24]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([NH2:14])=[O:13])=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCCCCNc1nc[nH]c1C(N)=O
Solvent: ClCCl
Product: CCCCCN(C(=S)NC(=O)c1ccccc1)c1nc[nH]c1C(N)=O
Reaction time: 8 h
Yield: 139.1 %

Procedure:
To a solution of 4-(pentylamino)-1H-imidazole-5-carboxamide (4.0 g, 0.020 mol) in DCM (50 mL) was added benzoyl isothiocyanate (3.3 mL, 0.024 mol). After being stirred overnight, the solid formed was filtered to give the crude product (10 g, ca 60% purity, 80% yield). This product was used for next step without further purification. LCMS calculated for C17H22N5O2S(M+H): 360.1; found: 360.1.
Reaction SMILES: [C:1](N1C[C@@H](S)[C@H](N(C)S(C2C=CC(OC3C=CC=CC=3)=CC=2)(=O)=O)C1)(=O)N.[C:28]([N:35]1[CH2:39][C@@H:38]([S:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(O[K])(C)(C)C.CI>CN(C=O)C.C(OCC)(=O)C>[C:28]([N:35]1[CH2:39][C@@H:38]([S:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([N:45]([CH3:1])[S:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:53][CH:54]=2)(=[O:47])=[O:48])[CH2:36]1)([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29]
Reactant: CN([C@@H]1CN(C(N)=O)C[C@H]1S)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1SC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
(±)-N-Carbamoyl-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-mercaptopyrrolidine. To a solution of (±)-N-Boc-trans-3-(4-phenoxybenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (236 mg, 0.466 mmol) in DMF (2 mL) at 0° C. was added tBuOK (0.69 mmol). The mixture was stirred at 0° C. for 10 min, then MeI (0.69 mmol) was added. The solution was stirred at 0° C. until TLC analysis showed no starting material remained. Ethyl acetate (20 mL) was added and the solution was extracted with water, then was dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (ethyl acetate) to give (±)-N-Boc-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-tertbutylmercaptopyrrolidine as a white powder (240 mg, 99%): 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J=8, 2H), 7.44 (t, J=8, 2H), 7.24 (t, J=8, 1H), 7.10 (m, 2H), 7.09 (d, J=9, 2H), 4.22 (m, 1H), 3.90 (m, 1H), 3.37 (m, 2H), 3.08 (m, 2H) 2.86 (s, 3H), 1.44 (s, 9H), 1.28 (s, 9H); MS (ESI) m/e 520.2 (M+); HRMS (ESI) calculated for C26H36N2O5S2Na+ 543.1950. found 543.1950.
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
2.8 G. of phosphorus trichloride in 20 ml. of pyridine are added to 5.2 g. of N-(2-aminoethyl)-morpholine in 80 ml. of pyridine at -5° C. over a period of 15 minutes, with stirring. The mixture is stirred for 30 minutes at -5° C. and 90 minutes at room temperature. Then, 3.1 g. of p-chlorobenzoic acid are added and the mixture is heated for 3 hours at 90° C. This mixture is evaporated to dryness and the residue is evaporated twice more with 100 ml. of toluene each time. The solid residue is taken up in 100 ml. of methylene chloride and 100 ml. of ice-water and the mixture is rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 1.3 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](C(F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(N3CCNCC3)=CC=N2)=CC=1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59]C1C=CC(N=C=O)=CC=1)[CH3:58]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:59][CH2:57][CH3:58])=[CH:23][CH:22]=4)=[O:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: CCOc1ccc(N=C=O)cc1
Agent: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (150 mg, 0.61 mmol), diisopropyl(ethyl)amine (158 mg, 1.22 mmol), and 4-ethoxyphenyl isocyanate (119 mg, 0.73 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].[N:31]1([C:37]2[N:38]=[C:39]([CH2:44][C:45]([O-])=[O:46])[NH:40][C:41](=[O:43])[CH:42]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Na+]>CN(C)C=O>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:45](=[O:46])[CH2:44][C:39]1[NH:40][C:41](=[O:43])[CH:42]=[C:37]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:38]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COCCOc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCCOc1ccccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 303 mg of 2-(2-methoxyethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 223 mg of N-[2-(2-methoxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:10]([Cl:9])(=[O:12])=[O:11]
Reactant: Cc1ccc(Br)cc1
Reactant: O=S(=O)(O)Cl
Product: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Temperature: 0 °C

Procedure:
40 g of 4-bromotoluene are slowly introduced into 250 ml of chlorosulfonic acid at −10° C. with stirring. The mixture is stirred at this temperature for 30 minutes, allowed to warm to 0° C. and poured on to excess ice. The product is filtered off with suction and washed with a little water. It is dried over P4O10 in vacuo and 63 g of a colorless solid are obtained, which is directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]2=[N:15][C:14]=1[CH3:28].[CH2:29]1COCC1.[Li]C(C)(C)C.CI>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:29])[N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C:16]2=[N:15][C:14]=1[CH3:28]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nc(C)nn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 42 %

Procedure:
To a −78° C. solution of 3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.72 mmol) and THF (5 mL) is added 1.7 M tert-BuLi (0.47 mL, 0.80 mmol). After 15 minutes MeI (0.052 mL, 0.83 mmol) is added and the solution warmed to ambient temperature. The solution is diluted with EtOAc (40 mL), washed with brine (40 mL), dried over MgSO4, filtered and concentrated. The solution is recrystallized from acetone:hexane furnish the title compound (0.13 g, 0.30 mmol, 42%). 1H NMR (CDCl3) δ0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.36 (s, 3H), 2.51 (s, 6H), 3.27-3.39 (m, 1H), 3.40 (s, 3H), 6.72 (s, 1H), 8.02 (s, 1H). LC/MS (m/z): calcd. for C21H25ClN6S (M+H)+: 429.2; found: 429.2.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C.CCOCC>CC(=O)CC>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:5][CH2:4]1.[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCc2c[nH]c3ccc(F)cc23)CC1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
In the manner described for Example 21, 240 mg (0.55 mmol.) of the polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide were also obtained (m.p. 160–163° C.) and were dissolved in 2-butanone (7 ml); chlorotrimethylsilane (105 μl, 0.83 mmol.) was added thereto. There immediately formed a pale precipitate, which was deposited in a tacky manner on the wall of the flask. The solvent was reduced to about 3 ml in vacuo and, after addition of ether (3 ml), vigorous stirring was carried out for 1 h at RT. The solid that formed was filtered off with suction, washed with ether (3×1.5 ml) and dried in vacuo. The hydrochloride of the polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide was thus obtained in the form of a hygroscopic solid in a yield of 234 mg.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][C@H:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14](C(=O)C)[C:15]=2[CH:16]=1)[CH3:2].N>C1COCC1.CO>[CH2:1]([C:3]12[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][NH:14][C:15]=2[CH:16]=1)[CH3:2]
Reactant: CC[C@]12CCC3(C[C@H]1CCOc1cc4c(cnn4C(C)=O)cc12)OCCO3
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCC12CCC3(CC1CCOc1cc4[nH]ncc4cc12)OCCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A solution of rac-1-((4aR,12bS)-12b-ethyl-1,4,4a,5,6,12b-hexahydro spiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolan]-9(2H)-yl)ethanone (89, R2=Ethyl) (3.02 g, 8.15 mmol) in a mixture of THF (54 mL) and MeOH (27 mL) was treated with ammonia (7 M in MeOH, 3.49 mL, 24.5 mmol) and stirred at rt overnight. The reaction mixture was concentrated under reduced pressure to give rac-(4aR,12bS)-12b-ethyl-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (90, R2=Ethyl) (2.68 g, 100%). The material was used without further purification. LC/MS, method 3, 2.09 min, MS m/z 329 (M+1)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.57 (s, 1H), 7.07 (s, 1H), 4.33-4.24 (m, 1H), 4.00-3.84 (m, 4H), 3.75-3.64 (m, 1H), 2.79-2.66 (m, 1H), 2.51-2.40 (m, 1H), 2.33-2.19 (m, 2H), 2.09-1.98 (m, 1H), 1.88-1.78 (m, 1H), 1.76-1.29 (m, 5H), (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([OH:11])[OH:10])=[CH:4][CH:3]=1.C([O-])([O-])O[CH2:15][CH3:16].O.[C:20]1(C)C=CC(S(O)(=O)=O)=C[CH:21]=1>ClCCl>[CH2:20]([O:11][CH:9]([O:10][CH2:15][CH3:16])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:12])[CH3:21]
Reactant: CCOC([O-])[O-]
Reactant: O=C(c1ccc(F)cc1)C(O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(OCC)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2,2-dihydroxyethanone (4.0 g, 0.024 mol), ethyl orthoformate (7.3 g, 49 mmol), and p-toluenesulfonic acid monohydrate (200 g, 1.05 mol) in dichloromethane (50 mL) was refluxed for 40 min. After cooling to room temperature (RT), the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with dichloromethane to give the desired product (5.2 g). 1H-NMR (300 MHz, CDCl3): 8.18-8.25 (m, 2H), 7.08-7.16 (m, 2H), 5.18 (s, 1H), 3.58-3.82 (m, 4H), 1.25 (t, J=7.0 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([Cl:24])[CH:15]=1.C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([Cl:24])[CH:15]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: CS(=O)(=O)c1ccc(CBr)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Cn2cc(Cl)cc(C(N)=O)c2=N)cc1Cl
Product: Cl
Temperature: 25 °C
Yield: 27.2 %

Procedure:
A solution of 2-amino-5-chloronicotinamide (200 mg) and 4-(bromomethyl)-2-chloro-1-(methylsulfonyl)benzene (430 mg) in DMF (3 ml) was stirred at 100° C. for 4 hr. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 1N sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=9:1→1:0). The obtained yellow solid was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution was added, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (65 mg).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:21]=[CH:20][CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:29])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:29][CH:9]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:21]=[CH:20][CH:19]=3)[C:15]=2[CH2:16][CH2:17][NH:8]1
Reactant: CC1c2ncnc(-c3ccnn3C3CCCCO3)c2CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1NCCc2c(-c3ccnn3C3CCCCO3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To the product of Example 112, step f (356 mg, 0.91 mmol) in EtOH (9 mL) was added a catalytic amount of 10% Pd/C Degussa type followed by a balloon of hydrogen gas. The mixture was stirred at room temperature overnight. The balloon was refilled with hydrogen gas and an additional spatula tip of 10% Pd/C was added. After an additional 24 h and the reaction was complete. The catalyst was removed by filtration and the liquid was concentrated in vacuo to afford the desired product (268 mg, 98%). MS (ESI) mass calcd. C16H21N5O, 299.2. m/z found 300.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([C:11]#[C:12][CH2:13]OC)=[CH:9][C:8]([C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:24][CH3:25])=[N:7][C:6]=1[CH3:26])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:8]([C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:24][CH3:25])=[N:7][C:6]=1[CH3:26])[CH3:2]
Reactant: CCOC(=O)c1c(C#CCOC)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(-c2c(CC)cccc2CC)nc(C)c1C(=O)OCC
Reaction time: 18 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-(3-methoxy-prop-1-ynyl)-2-methyl-nicotinic acid ethyl ester (160 mg, 0.44 mmol) and 10% Pd/C (40 mg, 25 wt %) in MeOH (20 mL) is hydrogenated for 18 hours at 55 psi (Parr shaker). After filtration through celite, the filtrate is concentrated in vacuo and the residue purified by flash chromatography to give 6-(2,6-diethyl)-4-(3-methoxypropyl)-2-methyl-nicotinic acid ethyl ester and 6-(2,6-diethyl-phenyl)-2-methyl-4-propyl-nicotinic acid ethyl ester. 6-(2,6-Diethyl)-4-(3-methoxypropyl)-2-methyl-nicotinic acid ethyl ester: 1H NMR (CDCl3) 7.26 (t, 1H), 7.12 (d, 2H), 7.00 (s, 1H), 4.43 (q, 2H), 3.37 (t, 2H), 3.30 (s, 3H), 2.72 (t, 2H), 2.59 (s, 3H), 2.38-2.25 (m, 4H), 1.92-1.83 (m, 2H), 1.41 (t, 3H), 1.04 (t, 6H). 6-(2,6-Diethyl-phenyl)-2-methyl-4-propyl-nicotinic acid ethyl ester: 1H NMR (CDCl3) 7.25 (t, 1H), 7.18 (d, 2H), 6.99 (s, 1H), 4.43 (q, 2H), 2.62 (q, 2H), 2.60 (s, 3H), 2.38-2.27 (m, 4H), 1.64 (q, 2H), 1.42 (t, 3H), 1.13 (t, 6H), 0.95 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][C@@H:13]([CH3:14])[CH2:16][CH3:17])=[O:6]
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC[C@H](C)COC(=O)c1ccc(O)c(F)c1
Reaction time: 8 h
Yield: 66 %

Procedure:
In a 250-ml, round-bottomed flask equipped with a heating mantle, magnetic stirrer, condenser and Dean Stark trap, were placed 2.5 g (16.0 mmol) of 3-fluoro-4-hydroxybenzoic acid, ten g (113.4 mmol) of (S)-2-methyl-1-butanol, 0.347 g of p-toluenesulfonic acid monohydrate and 100 ml of benzene. The reaction mixture was stirred overnight under reflux. The reaction mixture was extracted using saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered through cotton and evaporated to an oil. The product was purified by flash chromatography on silica gel with 3% diethyl ether in dichloromethane. Fractions containing the desired product were combined and evaporated to a pale-yellow oil. Analysis by NMR showed that considerable starting alcohol remained. The oil was placed under vacuum (at 70° C.) for two days. No alcohol was shown by gas chromatography to be present. The desired product was obtained in the amount of 2.39 g (66% yield) and had the following structure. ##STR30##