Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20]C)=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[CH3:23][NH:24][CH3:25].O>CO.S(=O)(=O)(O)O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[N:24]([CH3:25])[CH3:23])(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (6 g; 18.6474 mmole) in 33% w/w dimethylamine in methanol (50 ml) was heated at 100° C. under pressure (autoclaved) for 24 hours. The mixture was cooled, and treated with water, concentrated, and extracted with chloroform. The extract was washed with water, dried and evaporated to give a brown solid. The solid was heated in 70% sulphuric acid (150 ml) on a steambath for 6 hours. The mixture was cooled and the pH adjusted to about 7 before extraction into chloroform. The extract was dried and evaporated to give a yellow solid (1.25 g). NMR and mass spectra were consistent with the required structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[CH:13](O)[C@@H:14](C(O)=O)[NH:15][CH:16]=[O:17].COC(OC)N(C)C>C(Cl)(Cl)Cl>[CH:16]([NH:15]/[CH:14]=[CH:13]/[C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:17]
Reactant: COc1ccc2c(c1C(O)[C@H](NC=O)C(=O)O)CCCC2
Agent: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1/C=C/NC=O)CCCC2
Yield: 85 %

Procedure:
A solution of 3-(2-methoxy-5, 6, 7, 8-tetrahydronaphth-1-yl)-N-formylserine (2930 mg, 10 mmol) and N,N-dimethylformamide dimethyl acetal (7100 mg, 60 mmol) in dry chloroform (50 ml) is heated at reflux temperature for 2 hrs. The reaction mixture is evaporated under vacuum, the residue dissolved in chloroform and filtered through a silica gel column. The eluateis evaporated under vacuum to give almost pure title compound in 85% yield (1970 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>CO>[NH2:17][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCCOCn1cc(I)c2c(Cl)ncnc21
Solvent: CO
Product: Nc1ncnc2c1c(I)cn2COCCO
Temperature: 130 °C

Procedure:
4-Chloro-5-iodo-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]-pyrimidine (9b, 0.3 g) was covered with methanol saturated with ammonia (25 mL) and the reaction mixture was heated at 130° C. in a sealed vessel for 10 hours. The solvent was concentrated in vacuo to give a semi-solid mass which was recrystallized from methanol to afford 12, 0.20 g (71.4%), mp 169°-170° C. 1H NMR (DMSO-d6): δ8.7 (s, 1, C2--H), 8.3 (s, 1, C6--H), 5.7 (s, 2, N7--CH2) 4.6 (t, 1, exchangeable with D2O, OH): UVδmax nm (ε×104): (pH 7) 210 (2.0), 280 (0.9); (pH 1) 230 (1.8), 279 (0.9); (pH 11) 228 (0.9), 278 (0.9 ). Anal. Calcd. for C9H11N4O2I; C, 32.43; H, 3.30; N, 16.81. Found: C, 32.49; H, 3.58; N, 16.70.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:39]#[C:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]#[C:39][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:42][CH:43]=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu+2]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(Cl)cc2)CCN(C)C1
Temperature: 80 °C
Yield: 11.3 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in toluene (8-10 mL). Copper sulfate (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), potassium phosphate (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) was added and the mixture flushed with nitrogen. The reaction mixture was heated at 80° C. overnight (16 h). Product was detected by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The combined organic layer was concentrated under vacuum to obtain product, which was purified by column chromatography (Silica gel-60-80% EtOAc in hexane) to obtain product (38 mg) as a yellow solid. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.52-7.40 (m, 3H), 7.36-7.30(m, 2H), 7.20 (s, 1H), 7.12-7.09 (d, 1H), 3.77 (s, 2H), 3.06-2.94 (m, 4H), 2.62 (s, 3H), 2.42(s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11].[Cl:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+]>CN(C)C=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11]
Reactant: OCCCCl
Reactant: COc1ccc(F)cc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1COCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.870 g (5.00 mmol) of 2-chloromethyl-4-fluoro-1-methoxy-benzene [B. Maziere, N. Dat-Xuong, Chim. Ther. (3), 1-9(1968)]and 0.83 ml of 3-chloro-1-propanol were dissolved in 4.8 ml of N,N-dimethylformamide. 0.267 g (6.23 mmol) of sodium hydride (55% dispersion in mineral oil) was added in small portions over 2 hours keeping the temperature at 10-15° C. After 1 hour stirring at room temperature, 0.032 g (0.75 mmol) of sodium hydride dispersion was added and the mixture stirred another 3 hours. Thereupon, the reaction mixture was poured into 50 ml of ice-water and extracted three times with 100 ml of ether. The combined ether phases were subsequently washed with water, dried over magnesium sulphate and evaporated on a rotary evaporator at a maximum 40° C. The residue (1.5 g) which was thereby obtained was chromatographed on silica gel with dichloromethane/hexane (1:1). There was thus obtained 0.928 g (3.99 mmol), 80%,2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene as a colorless oil: MS: 232, 234 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:24].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:19][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:33]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=4[F:25])[C:3]3=[O:24])[CH2:8][CH2:9]2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 130 °C
Yield: 1.4 %

Procedure:
To a solution of (S)-3-amino-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 150, Step C, 0.30 g, 0.83 mmol) in DMSO (3 mL) was added 3,4-difluorobenzonitrile (0.35 g, 2.5 mmol) and potassium carbonate (0.34 g, 2.5 mmol) and the reaction was heated to 130° C. for 6 hours. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL), and brine (20 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of 1:9 to 1:4 EtOAc:DCM as eluent to give a solid, which was further triturated with DCM to give (S)-4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylamino)-3-fluorobenzonitrile (0.006 g, 0.012 mmol, 2% yield). Mass spectrum (apci) m/z=482.0, 483.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[N:55]([C@H:58]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:59])=[C:56]=[O:57]>>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[C:56](=[O:57])[NH:55][C@H:58]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:59])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: C[C@H](N=C=O)c1ccccc1
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)N[C@@H](C)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester was reacted with (S)-1-isocyanato-ethyl-benzene according to General Procedure I to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 902.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][S:15][C:14](=[O:17])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:15][C:14]2=[O:17])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: COc1ccc(C2=NNC(=O)SC2)cc1OC
Product: COc1ccc(C2=NN(Cc3ccc([N+](=O)[O-])cc3)C(=O)SC2)cc1OC

Procedure:
In analogy to Example 1, the reaction of 5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one ("B") with 4-nitrobenzyl chloride gives 3-(4-nitrobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 155°.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]=2[CH:1]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc2c(c1)Cc1ccccc1CO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2c(c1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol (14 g) and triethylamine (6.7 g) in 200 ml of dry dichloromethane was treated with methanesulfonylchloride (5.2 ml) and stirred at room temperature for 2 hours. This solution was evaporated to a paste, taken up in ethyl acetate, washed dried, and evaporated to an oil. Passage through a short pad of silica gel with chloroform as eluent gave 13.5 g of 2-(6,11-dihydrodibenz[b,e]-oxepin-2-yl)ethanol methanesulfonate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:15])([F:14])[C:11](O)=[O:12].O[N:24]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:15])([F:14])[C:11]([NH2:24])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 23.4 %

Procedure:
In 20 ml of dioxane were dissolved 300 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid and 110 mg of N-hydroxysuccinimide. To the resulting solution was added 200 mg of N,N'-dicyclohexylcarbodiimide. Then, the resulting mixture was subjected to reaction at 15°-25° C. for 3 hours. The reaction mixture was subjected to filtration to remove the insolubles, and 4.5 ml of a concentrated aqueous ammonia solution was added to the filtrate. The resulting mixture was subjected to reaction at 15°-25° C. for 20 hours. Then, the solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 10 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=10/1) to obtain 70 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[N:27]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)=[O:37])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:29][CH2:28][N:27]([CH2:33][CH2:34][NH:35][C:36](=[O:37])[C:38]2[CH:45]=[CH:44][C:41]([C:42]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:40][CH:39]=2)[CH2:32][CH2:31]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: O=Cc1ccc(C(=O)NCCN2CCOCC2)cc1
Product: O=C(NCCN1CCOCC1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 231 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(2-morpholinylethyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C31H34N6O3: 539.28; found: 539.63.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1.N1C=CN=C1.[C:44]([Si:48](Cl)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOCC.CCCCCC>[Si:48]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 3.5 h

Procedure:
To a mixture of 3α, 12α-dihydroxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (10.2 g), imidazole (1.64 g) and 4-dimethylaminopyridine (0.256 g) in dimethylformamide (30 ml) is added tert-butylchlorodiphenylsilane (6.04 g) and the mixture stirred for about 3.5 hours and diluted with ether/hexane (1:1). The solution is washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 50% ether in hexane to give the desired product.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([CH2:37][NH2:38])[OH:36]>CN(C=O)C>[OH:36][CH2:35][CH2:37][NH:38][C:1](=[O:22])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCCO
Reactant: CCCCCCCCC#CCC#CCC#CCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCCCCCCC#CCC#CCC#CCCCC(=O)NCCO
Reaction time: 2 h

Procedure:
A solution of 8 g of 5,8,11-eicosatriynoic acid and 5.62 g of carbonyldiimidazole in 40 cm3 of anhydrous DMF is brought to 80° C. for 3 hours under an inert atmosphere. 3.25 g of ethanolamine are then added at 0° C. After 2 hours, it is verified by thin layer chromatography that the starting acid is completely converted.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)[CH:31]=[C:30]([CH3:45])[CH:29]=3)[CH:27]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>ClCCl.[NH4+].[OH-]>[CH3:45][C:30]1[CH:29]=[C:28]([C:26]2[CH:27]=[C:22]([C:9]3([OH:8])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[CH:23]=[N:24][CH:25]=2)[CH:33]=[C:32]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=2)[CH:31]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCNCC3)c2)c1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (262 μL, 3.40 mmol) was added to a solution of tert-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidine-1-carboxylate (180 mg, 0.340 mmol) in dichloromethane (1.70 mL). The reaction mixture was stirred for 2 hours, diluted with 10% aqueous NH4OH (1.00 mL) and the precipitated solid was collected by filtration to yield 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidin-4-ol as a TFA salt. MS APCI calc'd for C22H23F3N5O [M+H]+ 430. found 430. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J=5.2 Hz, 1H), 8.66 (s, 2H), 8.01 (s, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.26 (d, J=5.0 Hz, 1H), 7.20 (s, 1H), 3.04-2.92 (m, 2H), 2.76 (br m, 2H), 2.36 (s, 3H), 1.99-1.75 (br m, 2H), 1.69-1.49 (br m, 2H).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:26][CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27]C)[CH:23]=5)[C:18]4=[O:29])=[CH:13][C:12]=3[F:30])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:26][CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:29])=[CH:13][C:12]=3[F:30])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N4CCCC4)C3)c(F)c1)C2=O
Agent: Br
Product: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
According to Method L, 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one was reacted with hydrogen bromide. In this way the product was obtained with molecular weight 395.48 (C23H26FN3O2); MS (ESI): 396 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH3:14]I>>[CH3:14][N:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]([NH2:11])[C:5]=2[CH:6]=[CH:7]1
Reactant: CI
Reactant: Cc1cc([N+](=O)[O-])c2cc[nH]c2c1
Product: Cc1cc(N)c2ccn(C)c2c1

Procedure:
In accordance with Example 9 (Steps 1 and 2), 6-methyl-4-nitro-1H-indole was used instead of 4-nitro-1H-indole, and methyl iodide was used instead of ethyl bromide-d5 to obtain 1,6-dimethyl-1H-indol-4-amine.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[OH-].[Na+].[Cl-].[CH2:9]([N+:11]1([CH2:16][CH3:17])[CH2:14][CH:13]([OH:15])[CH2:12]1)[CH3:10].Cl>O.CC(C)=O>[CH2:9]([N:11]([CH2:16][CH3:17])[CH2:12][CH:13]([OH:15])[CH2:14][S:3][CH2:2][C:1]([OH:5])=[O:4])[CH3:10]
Reactant: O=C(O)CS
Reactant: CC[N+]1(CC)CC(O)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC)CC(O)CSCC(=O)O
Temperature: 70 °C
Yield: 66.1 %

Procedure:
Into a solution of 18.4g of thioglycolic acid in 50cc of water neutralized by 16g of NaOH in 60cc of water, there is poured a solution of 33.1g of 1,1-diethyl-3-hydroxy azetidinium chloride in 90cc of water. The resulting mixture is heated for 5 hours at 70°C under a nitrogen atmosphere, at which time it is then neutralized by the addition thereto of 16.5cc of 12N HCl. The water is then expelled by distilling the reaction mixture under a vacuum and the residue is then taken up in 200 cc of isopropanol. After eliminating the sodium chloride precipitate by filtration, the resulting alcoholic filtrate is evaporated to dryness. The residue is then taken up in 100cc of water and filtered through a bed of DOWEX50W resin in order to eliminate residual traces of sodium chloride. The thus treated aqueous solution is then evaporated to dryness yielding an oil which when treated with acetone provides 29.2g of a whitish product product melting at 104°C.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:17][C:18]([O:20]CC)=O)[C@@H:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].C(N(CC)CC)C>CO>[O:3]=[C:2]1[NH:1][C:18](=[O:20])[CH2:17][N:4]1[C@@H:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N1CC(=O)NC1=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A solution containing the product from Example 46B (20.0 mmol) in methanol (30 mL) was treated with triethylamine (5.6 mL, 40.2 mmol), stirred at 50° C. for 2 hours, and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (4.57 g, 85% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8](S(C)(=O)=O)[C:5]2=[N:6][CH:7]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: CS(=O)(=O)n1ccc2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(-c2cnc3[nH]ccc3c2)ccn1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-1-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (140 mg, 0.51 mmol) and 4-pyridinyl boronic acid (125 mg, 1.02 mmol) in DMF (4 mL) was added aqueous Na2CO3 (2M, 1.3 mL, 2.6 mmol). To this suspension was then added PdCl2(dppf) (20 mg, 0.025 mmol) under N2 atmosphere. The flask was then covered with septa, heated at 80° C. for 9 h, and poured into water. The precipitate was collected by filtration, washed with water, and redissolved in MeOH (10 mL). To this Methanol solution was added 6N NaOH solution (2 mL) and the resulting basic reaction mixture was heated at 50° C. for 3 h. After evaporating the MeOH, the aqueous residue was acidified with 6N HCl to pH=2. The precipitate was filtered off and washed with 2N HCl. The acidic filtrate was then neutralized with saturated NaHCO3 solution. The crude product was collected by filtration, washed with water, and dried on the pump for direct use (60 mg, 0.31 mmol). LC/MS: Rt 1.96 mins.; m/e 196.1 (M+H).