Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42]Br)=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH:36]=[CH:35]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>CS(C)=O.O>[C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:42][C@@H:41]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:40])[NH:38]5)[O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 41 (0.117 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) and a solution of (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)-ethyl)quinolin-2(1H)-one (0.2 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) was added sodium hydrogen carbonate (0.103 g, 1.23 mmol) and sodium iodide (0.092 g, 0.61 mmol). The resulting reaction mixture was stirred at 150° C. for 1 hour. The mixture was poured into water and the precipitate was collected by filtration and washed with ether and ethyl acetate. The title compound was obtained as a brown solid (0.231 g, 57%) and was used in the next step without further purification. MS (M+): 694.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[SH:2][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1Cc2cc(S)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 5-chlorosulfonyl oxindole from the previous step, 42.23 g (182.3 mmol) was suspended in anhydrous dichloromethane (100 mL) in a 1 L round flask. The mixture was cooled on ice slush bath and a solution of triphenylphosphine 167.5 g (638 mmol, 3.5 eq.) in anhydrous dichloromethane (300 mL) was dropwise added from an addition funnel under nitrogen with cooling over a 45 min period. After complete addition the flask was removed from the cooling bath and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by water addition, 200 mL. The flask with the biphasic mixture was placed on a 50° C. water bath and the mixture was refluxed under nitrogen for 1 hour, then cooled on ice. The precipitated product was collected by filtration, washed thoroughly with ice-chilled dichloromethane and ice water, then dried by suction and on highvac, to provide 19.58 g of a pure product. The biphasic filtrates were de-oxygenated by argon/vacuum purge (3 times). The mixture was made strongly alkaline by addition of 50% aq. NaOH solution, shaken under Ar and then rapidly separated. The organic phase was re-extracted with water. The aqueous phases were promptly washed with fresh dichloromethane (200 mL). The combined aqueous extracts were made acidic by addition of 6M HCl, the mixture was cooled on ice, the precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac, to provide a second crop of the product, 7.15 g. The combined yield was 26.73 g (88.5% th) of a light tan solid. 1H-NMR (d6-DMSO, 400 MHz): 10.339 (s, 1H), 7.151 (s, 1H), 7.108 (m, 1H), 6.707 (d, 8.0 Hz, 1H), 5.109 (s, 1H), 3.436 (s, 2H)
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])#[N:2].[NH2:13][OH:14]>CCO>[NH2:2]/[C:1](=[N:13]/[OH:14])/[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCC#N
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC/C(N)=N\O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Tert-butyl N-(2-cyanoethyl)carbamate (40 g; 235 mmol; 1 eq.) and hydroxylamine (41.6 ml; 705 mmol; 3 eq.) are dissolved in EtOH (800 ml). The resulting solution is heated under reflux for 2 hours. The reaction progression is followed by 1H NMR. After 2 hours, the reaction mixture is cooled down to RT, concentrated under high vacuum to afford the title compound as a white solid (47.5 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C@H:27]([CH2:25][CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Yield: 19.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.6 g) described in Preparation Example 65 and (R)-4-ethyloxazolidin-2-one (553 mg) described in Preparation Example 26, the title compound (336 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:29]([CH:37]=O)[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1>>[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:29]([CH:37]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[NH:11][C:10]3=[O:16])[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)Nc1ccncc1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(-c2ccccc2)c1C(=O)Nc1ccncc1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid pyridin-4-ylamide to give the title compound.
Reaction SMILES: [ClH:1].Cl.Cl.[C:4]1([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:28][CH3:29].CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[ClH:1].[C:4]1([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH2:28][CH3:29])[CH2:23][CH2:22]3)=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCCN1CCNCC1)N1CCN(c2ccccc2)CC1
Reactant: CCI
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCN1CCN(CCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 170 °C
Yield: 142.5 %

Procedure:
2-(piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate (None HCl salt of Example 30; 291 mg, 0.91 mmol) was dissolved in DMF (2 mL). Iodoethane (74 μl, 2.31 mmol) and DIPEA (0.3 mL, 1.72 mmol) were added and the reaction mixture was heated at 170° C. for 15 minutes in a Biotage Initiator microwave at high absorption and then concentrated in vacuo. The residue was dissolved in 1 M aq Na2CO3 solution (25 mL) and extracted with DCM (3×25 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified normal phase column chromatography (eluting with DCM, followed by a 200:8:1 mixture of DCM:EtOH:NH3) followed by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-100%) to give a colourless oil. The oil was dissolved in DCM, treated with an excess of 2M HCl in Et2O and concentrated in vacuo to give 2-(4-ethylpiperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate trihydrochloride (197 mg, 52%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:31]>ClCCl.O1CCOCC1>[Cl:23][C:17]1[CH:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[C:21]#[N:22].[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(Cl)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC2CCNCC2)cc1Cl
Reaction time: 1 h

Procedure:
4-(3-Chloro-4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (290 mg; 0.87 mmol, prepared according to Example 103) is dissolved in dichloromethane (1.3 mL) and trifluoroacetic acid (0.7 mL) is added under stiffing. After 60 minutes, the reaction mixture is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (2×5 mL). The product is then diluted in dioxane (1 mL) and a 4N solution of hydrochloric acid in dioxane (2 mL) is added. The precipitate formed is filtered and dried under high vacuum at 40° C. to afford the desired product as hydrochloride (210 mg; 0.77 mmol).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]34[O:24][C:20]3([C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:21][CH2:22][CH2:23]4)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]3([OH:24])[CH2:23][CH2:22][CH2:21][CH:20]3[C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(C23CCCC2(Cc2nc(-c4ccccc4)c(-c4ccccc4)o2)O3)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1cccc(C2CCCC2(O)Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 24 h
Yield: 51.8 %

Procedure:
To a solution of ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]-1,2-epoxycyclopentyl]phenoxy]acetate (500 mg) in ethanol (20 ml) was added palladium on carbon (0.5 g). After being stirred for 24 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated in vacuo to give ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]-2-hydroxycyclopentyl]phenoxy]-acetate (260 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C:61](Cl)=[O:62])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][N:49]([C:61]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:62])[CH2:48]1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.0.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:7]1)([OH:3])=[O:2].C([SiH](CC)CC)C.C(Cl)Cl>C(OCC)(=O)C>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:7]1)([OH:3])=[O:2]
Reactant: O=C(O)CCn1cc(CCNS(=O)(=O)c2ccc(F)cc2)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)CCN1CC(CCNS(=O)(=O)c2ccc(F)cc2)c2ccccc21
Yield: 77.8 %

Procedure:
0.75 g (1.9 mmol) of N-[2-[1-(2-carboxyethyl)-1H-indol-3-yl]ethyl]-(4-fluorophenyl)sulphonamide are reduced with triethylsilane analogously to Example 1. 0.58 g of a viscous oily product is thus obtained (Rf =0.18, CH2Cl2 :ethyl acetate=100:2). After conversion of the product into its hydrochloride (analogously to Example 1), 0.62 g (76% of theory) of a solid residue is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:19]1([CH:25]=[CH:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:19]1([CH:25]=[CH:26][CH2:27][NH:28][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC=Cc1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
120 mg (0.450 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 71.9 mg (0.540 mmol) of 3-phenyl-2-propene-1-ylamine were dissolved in 10 ml of DMF. 129 mg (0.675 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:21]1[O:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1)[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:26]([C:24]3[N:25]=[C:21]([CH2:19][CH3:20])[O:22][C:23]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-ethyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[C:3]=1[Cl:15].[C:16]([Cu])#[N:17]>>[Cl:15][C:3]1[C:4]2[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:6][C:5]=2[CH:13]=[CH:14][C:2]=1[C:16]#[N:17]
Reactant: N#C[Cu]
Reactant: FC(F)(F)c1nc2c(Cl)c(Br)ccc2[nH]1
Product: N#Cc1ccc2[nH]c(C(F)(F)F)nc2c1Cl

Procedure:
Synthesized as described in Example 197A from 5-bromo-4-chloro-2-(trifluoromethyl)-1H-benzimidazole and CuCN: MS (APCl) m/z 246 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1C(=O)N([I:17])C(=O)C1>>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[I:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)nc(N)n1
Product: Nc1nc(N)c(I)c(Cl)n1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 25 g (173 mmol) 6-chloro-pyrimidine-2,4-diamine and 39 g (173 mmol) NIS. Yield after precipitation of the product from water: 38.8 g (83%).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:30])[CH2:22][CH2:23]1)[CH2:18][C@H:17]3[CH3:31].OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)C[C@H]2C.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)CC1)CC3>>[CH3:18][C@H:19]1[C@@:24]2([CH2:25][OH:26])[C:23]([CH2:31][CH2:17][C@@H:16]3[C@@H:27]2[CH2:28][CH2:29][C@@:11]2([CH3:12])[C@H:13]3[CH2:14][CH2:15][C@@H:10]2[OH:9])=[CH:22][C@H:21]([OH:30])[CH2:20]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)O
Product: C[C@@H]1C[C@@H](O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO

Procedure:
Following essentially the same procedure and substituting 17β,19-dihydroxy-7α-methyl-4-androsten-3-one diacetate, 7α-methyl-17β,19-di-(2'-tetrahydropyranyloxy)-4-androsten-3-one and 19-hydroxy-1β-methyl-4-androsten-3,17-dione for the 17β,19-dihydroxy-4-androsten-3-one above results in the preparation of 7α-methyl-4-androstene-3α,17β,19-triol 17β,19-diacetate, 7α-methyl-17β,19-di-(2'-tetrahydropyranyloxy)-4-androsten-3α-ol and 1β-methyl-4-androstene-3α,17β,19-triol, respectively.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.[ClH:22].CCOCC>CO>[ClH:21].[ClH:22].[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
A solution of 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine (6.38 g, 20.5 mmol) in CH3OH (80 mL) was treated with 1 N HCl-Et2O (100 mL) and was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure to afford a solid which was purified by recrystallization (1:2 CH3OH—CH3CN, 150 mL) to give 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride as a white powder (4.939 g, 84.9%): 1H NMR (d6-DMSO, 300 MHz) δ3.15 (br, 1H), 3.3-3.75 (br-m, 4H), 3.9 (br, 1H), 4.05 (br, 1H), 4.44 (br, 1H), 4.54 (br, 1H), 7.5-7.7 (m, 4H), 8.45 (br, 1H), 8.60 (br, 1H); The purity was determined by RPLC/MS (>99%); ESI/MS m/e 211.0 (M++H, C11H16ClN2).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:18])([CH3:17])[CH:11]=[C:10]2[CH3:19]>N1C=CC=CC=1>[C:1]([N:13]1[C:14]2[C:9](=[CH:8][C:7]([O:6][CH3:5])=[CH:16][CH:15]=2)[C:10]([CH3:19])=[CH:11][C:12]1([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(C)=CC(C)(C)N2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C)=CC(C)(C)N2C(C)=O
Reaction time: 18 h

Procedure:
Acetyl chloride (8 ml) was added dropwise to a cooled (0° C.) solution of 1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline (1.7 g) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (60 ml). After stirring for 18 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in dichloromethane as eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CCCCCC.[F:20][C:21]([F:29])([F:28])[C:22]([C:24]([F:27])([F:26])[F:25])=[O:23]>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22]([OH:23])([C:24]([F:27])([F:26])[F:25])[C:21]([F:29])([F:28])[F:20])[N:3]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cccc(Br)n1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
To a suspension of 2,6-dibromopyridine (2.37 g, 10 mmol) in THF (25 mL) at -70° there was added slowly n-BuLi, 1.4M, in hexane (7.9mL, 11 mmol). The resulting mixture was stirred in the cold until a solution was obtained (10 min). This solution was cannulated into a solution of hexafluoroacetone prepared by bubbling hexafluoroacetone into THF (10 mL) at -70° for 3 min. The resulting reaction mixture was stirred for 15 min., then quenched with an aqueous solution of NH4Cl (8 mL). The suspension was allowed to warm to r.t. and was extracted with Et2O. After drying and evaporation of the organic extract, the residue was chromatographed on silica gel with hexane:EtOAc, followed by bulb-to-bulb distillation to afford the title compound, m.p. 67°-69° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:12]2=[O:19])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CCCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCCCC1=Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of KOH (0.25 g, 4.46 mmol) in water (4.4 mL) was added to 4-fluoro-benzaldehyde Compound 3a (1.07 mL, 10 mmol) and the suspension was heated to 65° C. Cycloheptanone Compound 1a (1.18 mL, 10 mmol) was added dropwise over a period of 15 mins. The mixture was refluxed for 5 hrs, then stirred overnight at room temperature. The reaction mixture was acidified with 1N HCl (26 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over Na2SO4, then filtered and concentrated. The resulting yellow residue was purified on a silica gel column (using with 6% EtOAc/Hexane) to give 2-(4-fluoro-benzylidene)-cycloheptanone Compound 3b (1.1 g, 50.4%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:9]([NH:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1)[CH3:10]
Reactant: C1COCCN1
Reactant: CCNc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Product: CCNc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 80 %

Procedure:
A mixture of 80 mg (0.25 mmol) 6-chloro-2-ethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide and 433 mg (5.0 mmol) morpholine was heated in the microwave to 120° C. for 10 h. After cooling to RT, purification of the residue by CC (hexane/EtOAc 2:1) provided 73 mg (0.2 mmol, 78%) 2-Ethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 20). [M+H]+ 373.2.