Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:13]([Cl:30])=[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]3[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO.C(OCC)(=O)C>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:13]([Cl:30])=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2c(Cl)c3ccncn3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NOC[C@H](O)CO)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (57 mg, 0.1 mmol) in methanol (1 mL) was added a solution of hydrochloric acid in dioxane (1 mL, 4M, 4 mmol). The reaction was stirred at room temperature for 1 hour then diluted with ethyl acetate (5 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield a light brown solid. The solid was triturated with acetonitrile (3 mL) to yield the title compound as an off white solid (13 mg, 45%). 1H NMR (CH3 OH-d4): 8.74 (1H, d, J=1.57 Hz), 7.49 (1H, d, J=6.61 Hz), 7.42 (1H, dd, J=10.78, 1.91 Hz), 7.38 (1H, dd, J=6.61, 1.58 Hz), 7.21 (1H, ddd, J=8.48, 1.90, 1.11 Hz), 6.14 (1H, t, J=8.76 Hz), 3.89-3.80 (1H, m), 3.79-3.71 (2H, m), 3.56-3.42 (2H, m). LCMS (Method A): RT=7.70 min, M+H+=521.
Reaction SMILES: ClC1C=C2C(C3N=C(N[C@H]4CCCN(CC(O)COC)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.[Cl:41][C:42]1[CH:43]=[C:44]2[C:50]([C:51]3[N:56]=[C:55]([NH:57][CH:58]4[CH2:63][CH2:62][CH2:61][CH2:60][N:59]4[CH:64]([O:68][CH3:69])[C@@H:65]([OH:67])[CH3:66])[C:54]([F:70])=[CH:53][N:52]=3)=[CH:49][N:48](S(C3C=CC(C)=CC=3)(=O)=O)[C:45]2=[N:46][CH:47]=1.[Li+].[OH-]>C1COCC1.O>[Cl:41][C:42]1[CH:43]=[C:44]2[C:50]([C:51]3[N:56]=[C:55]([NH:57][CH:58]4[CH2:63][CH2:62][CH2:61][CH2:60][N:59]4[CH:64]([O:68][CH3:69])[C@@H:65]([OH:67])[CH3:66])[C:54]([F:70])=[CH:53][N:52]=3)=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1
Reactant: COC([C@H](C)O)N1CCCCC1Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Cl)cc23)ncc1F
Agent: COCC(O)CN1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC([C@H](C)O)N1CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 120 °C

Procedure:
To a solution of 1-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]-3-methoxy-propan-2-ol, 1d, (0.15 g, 0.24 mmol) in THF was added 1N LiOH solution. The reaction mixture was heated in a microwave reactor at 120° C. for 5 minutes. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc (twice). The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo. The resulting solid was purified by silica gel chromatography (5-20% MeOH: CH2Cl2) to afford the desired product (537) as a white solid.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:37][C:34]2[NH:35][N:36]=[C:32]([O:31][CH2:30][C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:33]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N2CCN3CCCC3C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN5CCCC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 27 %

Procedure:
4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as for Example 159, but starting from methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (0.25 g, 0.96 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.239 g, 0.96 mmol) and 2M trimethylaluminium in toluene (1.2 ml, 2.4 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.124 g, 27%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:37][CH2:36][C:35]1[N:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:45])[NH:21][C:9]4[CH:10]=[C:11]([C:19]#[N:20])[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[N:32]=[N:33][CH:34]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-cyano-5-(isopropyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M96) (0.45 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (236 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:8]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:36]1[N:43]=[CH:42][CH:41]=[CH:40][C:37]=1[C:38]#[N:39]>CN(C)C=O.O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:8]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C:36]3[N:43]=[CH:42][CH:41]=[CH:40][C:37]=3[C:38]#[N:39])=[CH:26][CH:27]=1)=[CH:7]2
Reactant: N#Cc1cccnc1Cl
Reactant: O=c1c2c(Cl)cccc2cc(-c2ccc(O)cc2)n1Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cccnc1Oc1ccc(-c2cc3cccc(Cl)c3c(=O)n2Cc2ccc(F)cc2F)cc1
Temperature: 105 °C
Yield: 57 %

Procedure:
To a solution of 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (54 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL), was added powdered Cs2CO3 (89 mg, 0.27 mmol), followed by 2-chloronicotinonitrile (33 mg, 0.23 mmol). The resulting suspension was stirred and heated in a 105° C. oil bath. After stirring for 64 h at 105° C., HPLC analysis of the reaction mixture showed no 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, nor 2-chloronicotinonitrile remaining. The reaction was allowed to cool to ambient temperature and was diluted with H2O (15 mL), and Et2O (50 mL). The layers were separated, the organic layer was washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a yellow liquid. The crude product was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 10% to 40% EtOAc/hexane. The product peak was collected to afford 2-{4-[8-chloro-2-(2,4-difluorobenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]phenoxy}nicotinonitrile, a compound of formula (Id), (36 mg, 57% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.35 (1H, dd, J=5.0, 2.0 Hz), 8.05 (1H, dd, J=7.6, 1.8 Hz), 7.54-7.51 (2H, m), 7.42-7.38 (1 H, m), 7.27-7.24 (2H, m), 7.22-7.18 (2H, m), 7.15 (1H, dd, J=7.6, 5.0 Hz), 7.08-7.00 (1H, m), 6.80-6.74 (1H, m), 6.71-6.65 (1H, m), 6.46 (1H, s), 5.22 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#N)=[N:6][CH:7]=1.Cl.[C:11]([O-])(O)=[O:12].[Na+].C[OH:17]>>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:12][CH3:11])=[O:17])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(F)cn1
Reactant: CO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ncc(F)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 5-fluoropyrimidine-2-carbonitrile (513 mg, 4.17 mmol) in MeOH (5 mL) was added 5 mL of concentrated HCl. The mixture was stirred at 80° C. for 2 h. The solution was allowed to cool to room temperature and then treated with a small amount of saturated aqueous NaHCO3 solution and a larger amount of solid NaHCO3. The solution was used to keep everything homogeneous. When the pH reached 6-7 the aqueous layer was extracted with 10% EtOAc/DCM. The combined organic layers containing the ester were dried over Na2SO4. The aqueous layer was acidified to pH 3-4 with 1N HCl and then extracted with 10% EtOAc/DCM to afford the acid. The ester layer was filtered, concentrated in vacuo to a white solid (460 mg, 71%). MS (ESI): mass calcd. C6H5FN2O2, 156.03; m/z found, 157.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.80 (s, 2H), 4.07 (s, 3H).
Reaction SMILES: [I-].[CH2:2]([N+:4]1(C)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH3:3].[CH2:12]([O:14][C@H:15]1[CH2:20]C[C@H](N)[CH2:17][CH2:16]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:12]([O:14][C@H:15]1[CH2:20][CH2:3][C@H:2]([N:4]2[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]2)[CH2:17][CH2:16]1)[CH3:13]
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: CCO[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCO[C@H]1CC[C@H](N2CCC(=O)CC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-ethyl-4-piperidone methiodide (D9, 27 g), trans-4-ethoxycyclohexylamine (D65, 8.16 g, 0.065 mol), potassium carbonate (13.5 g), water (100 mL), and ethanol (200 mL) was heated for 3 hours at 80° C., then cooled overnight. The mixture was partitioned with aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was separated, washed with brine and solvent removed to give the title compound as an amber coloured oil (13.2 g).
Reaction SMILES: [CH3:1][CH:2]1O[CH:5]([CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[H][H]>O>[C:13]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCOC(=O)CCCC(=O)CCC1CCC(C)O1
Solvent: O
Product: CCCCCCCCCCCC(=O)OCC

Procedure:
Neat ethyl 7-(5-methyltetrahydrofuran-2-yl)-5-oxoheptanoate was flowed at a pressure of 470 psig, and temperature of 240° C. under flowing hydrogen gas for 28 hours. The liquid flow rate and hydrogen gas flow rates were kept constant relative to each other, e.g. 0.03 mL/min liquid flow and 30 mL/min gas flow; 0.06 and 60 mL/min; or 0.09 and 90 mL/min The effluent was primarily organic with a small spontaneously separating water layer beneath the organic phase. Not counting the startup and shutdown, 62.9 g of organic phase was collected out of a theoretical 68.5 g, or 91.9%. GCMS analysis revealed an initial high concentration of 58.2% ethyl dodecanoate, 28.7% dodecanoic acid, and 13% intermediates, possibly ethyl 7-(5-methyltetrahydrofuran-2-yl)heptanoate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[SH:29][CH2:30][C@@H:31]([CH3:42])[C:32]([N:34]1[C@H:38]([C:39]([OH:41])=[O:40])[CH2:37][S:36][CH2:35]1)=[O:33]>O1CCCC1.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([S:29][CH2:30][C@@H:31]([CH3:42])[C:32]([N:34]2[C@H:38]([C:39]([OH:41])=[O:40])[CH2:37][S:36][CH2:35]2)=[O:33])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](CS)C(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)SC[C@@H](C)C(=O)N2CSC[C@H]2C(=O)O)cc1
Temperature: -5 °C

Procedure:
1.8 g of 4-acetylaminobenzoic acid is dissolved in 20 ml of dry tetrahydrofuran. To this solution, 1.4 ml of triethylamine is added. To this mixture, 1.3 ml of isobutyl chloroformate is added dropwise with stirring at -5° C. After ten minutes, to this solution, 20 ml of aqueous solution of 2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 1.4 ml of triethylamine is added, and the mixture is stirred at room temperature for 30 min. To this reaction solution, 40 ml of water is added, and the obtained mixture is washed with ethyl acetate. The aqueous layer is acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.1 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 3.6 g (90%), mp. 206°-207° C. (methanol), [α]D27 -152.5° (c=1.0, methanol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([CH3:29])=[N:10][CH:11]=[C:12]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][C:12]3[CH:13]=[C:8]([NH2:7])[C:9]([CH3:29])=[N:10][CH:11]=3)=[N:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)OC(C)(C)C)c3)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(N)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{5-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-yl}-carbamic acid tert-butyl ester 11 (0.33 mmol) is dissolved in DCM (2 mL) and treated with TFA (3 mL). The reaction mix is stirred at rt for 2 h. The solvent is removed to afford an off white solid residue. The residue is taken in water, the pH neutralized with 5% Na2CO3 and extracted with DCM:IPA=3:1 (3×40 mL). The organic layer is washed with brine and dried over Na2SO4. Evaporation of the organic solvent under reduced pressure affords N5-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-2-methyl-pyridine-3,5-diamine 12, which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 10.37 (s, 1H), 8.90 (s, 2H), 8.47 (bs, 1H), 7.79 (bs, 1H), 7.71-7.69 (m, 2H), 7.08-7.06 (m, 2H), 6.36 (bs, 2H), 3.81 (s, 3H), 2.43 (s, 3H). MS (m/z) (M+1)+: 308.2.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:29]1[CH2:42][O:41][C:36]23[O:37][CH2:38][CH2:39][O:40][C:31]2([C@:32]2([CH2:55][CH2:54][C@H:53]4[C@@H:43]([CH2:44][C:45](=[CH2:56])[CH:46]5[C@:51]4([CH3:52])[CH2:50][CH2:49][CH2:48][CH2:47]5)[C@@H:34]2[CH2:35]3)[CH3:33])[O:30]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:39]1[CH2:38][O:37][C:36]23[O:41][CH2:42][CH2:29][O:30][C:31]2([C@:32]2([CH2:55][CH2:54][C@H:53]4[C@@H:43]([CH2:44]/[C:45](=[CH:56]\[CH3:1])/[CH:46]5[C@:51]4([CH3:52])[CH2:50][CH2:49][CH2:48][CH2:47]5)[C@@H:34]2[CH2:35]3)[CH3:33])[O:40]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCCCC1C(=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C/C=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Yield: 96 %

Procedure:
17,17-Bis(ethylendioxy)-6(E)-ethylidenandrostane was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)androstane-6-one and (ethyl)triphenylphosphonium bromide by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 8). The mixture was purified by flash chromatography (SiO2, cyclohexane/EtOAc 85/15). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.91 (m, 1H), 3.93-3.78 (m, 8H), 2.69 (m, 1H), 2.10-0.85 (m, 22H), 0.81 (s, 3H), 0.66 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(Cl)(=O)C(Cl)=O>>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:13]3[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18]3)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncoc2c1
Reactant: C1=CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: O=C(c1ccc2ncoc2c1)N1CC=CCC1

Procedure:
Coupling of 1,3-benzoxazol-6-carboxylic acid with 1,2,3,6-tetrahydropyridine is performed in the same manner as described for the preparation of Invention Compound V through activation with carbonyl diimidazole or by activation with other suitable reagents such as oxalyl chloride. The product can be isolated by the same methods as described for the isolation of Invention Compound V and purified by chromatography on silica gel. EIMS m/z=228 (parent), 146 (base), and 118. 1H NMR δ 2.2 (br, 2), 3.4-4.3 (br m, 4), 5.7-5.95 (br m, 2), 7.52 (dd, 1, J=8.39, 1.49 Hz), 7.64 (d, 1, J=8.41 Hz), 7.87 (d, 1, J=1.32 Hz), and 8.16 ppm (s, 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41]>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41])=[O:29]
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C(Br)CBr
Product: COc1ccc(OC)c(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)N[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1Br
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of 2-bromo-5-chloro-benzoic acid (2.5 g, 10.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 6 ml, 12 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (10 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:2) to provide methyl 2-bromo-5-chloro-benzoate (2.1 g, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[S:10])[CH:3]=1.[NH3:11]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: N
Solvent: C1COCCO1
Product: NC(=S)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.16 h
Yield: 89 %

Procedure:
1-Chloro-3-isothiocyanatobenzene (15 g, 88 mmol) was added to a solution of 0.5 M ammonia in 1,4-dioxane (80 mL), and the mixture was stirred at room temperature for 0.16 h. The reaction mixture was concentrated in vacuo, and partitioned between ethyl acetate and water. The separated organic layer was washed with saturated NaCl solution, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo to afford the title compound (15.5 g, 89%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.70 (s, 1H), 7.52 (bs, 2H), 7.38-7.27 (m, 2H), 7.15 (dt, J1=7.0 Hz, J2=2.1 Hz, 1H). ESI-MS m/z: 187 (M+H)+.
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[F:18][C:13]1[CH:12]=[C:11]([CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[C:3]([NH:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: CCCCCCN
Reactant: COC(=O)C(c1ccc(F)c(F)c1)c1ccccn1
Product: CCCCCCNC(=O)C(c1ccc(F)c(F)c1)c1ccccn1

Procedure:
The title compound, amorphous, MS: m/e=333.3 (M+H+) was prepared in accordance with the general method of example 22(a) from (RS)-2-(3,4-difluoro-phenyl)-2-pyridin-2-yl-acetic acid methyl ester and hexylamine.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[C:14]1([C:20]2NN=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C:20]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Yield: 82 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (6.81 g), 5-phenyl-1H-tetrazole (5.01 g) and pyridine (10 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration, and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with cold hexane to give methyl 4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzoate (7.88 g, yield 82%). Recrystallization from hexane-tetrahydrofuran gave colorless crystals. melting point: 172–173° C.
Reaction SMILES: Cl.[C:2]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[O:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:2]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[O:28][CH2:27][CH2:26][N:25]([CH3:31])[CH2:24]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(OCC2CNCCO2)c(NC(=O)Nc2cnc(C#N)cn2)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OCC2CN(C)CCO2)c(NC(=O)Nc2cnc(C#N)cn2)c1
Reaction time: 12 h
Yield: 28.4 %

Procedure:
A solution of 1-(5-cyano-pyrazin-2-yl)-3-[5-methyl-2-(morpholin-2-ylmethoxy)-phenyl]-urea hydrochloride salt (0.0104 g, 0.129 mmol) in MeOH (1 mL) was cooled to 0° C. and treated with an aqueous solution of formaldehyde (0.12 mmol) followed by sodium triacetoxy borohydride (0.06 g, 0.292 mmol). The reaction was stirred for 12 h, then concentrated in vacuo. The residue was chromatographed on silica (2% MeOH in CH2Cl2) to give the product as a white solid (0.014 g). 1H-NMR (400 MHz, d6-DMSO) δ 10.90 (s, 1, H), 10 (br s, 1, H), 8.9 (s, 1, H), 8.8 (s, 1, H), 8 (s, 1, H), 6.9 (m, 1, H), 6.8 μm, 1, H), 3.9 (m, 4, H), 3.6 (t, 1, H), 2.9 (d, 1, H), 2.7 (d, 1, H), 2.2 (s, 3, H), 2.1 (s, 3, H), 2 (t, 1, H), 1.8 (t, 1, H). LRMS (esi, positive) m/e 383.40 (M+1).