Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:29]1[CH2:30][C@@H:31]([OH:32])[C@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:28]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: CC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[CH3:2].FC(F)(F)C(O)=O.[N+:22]([O-])([OH:24])=[O:23].N.O>>[CH2:13]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:22]([O-:24])=[O:23])[CH:10]=2)[CH2:5]1)[CH3:14]
Reactant: CCN(CC)C1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCN(CC)C1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 7.5 °C
Reaction time: 5 h

Procedure:
To a solution of Example 226A (2.0 g, 10.57 mmol) in trifluoroacetic acid (80 ml, 1038 mmol) was added nitric acid (0.726 ml, 10.57 mmol) dropwise at 0° C. The mixture was stirred at 0-15° C. for 5 hours. The solution was poured into ice/water (20 mL) and the pH was adjusted to 10 with NH3/H2O. The mixture was extracted with methylene chloride (4×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide the title compound.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH:15]=[CH2:16].CO>C1(C)C=CC=CC=1>[C:14]([CH2:15][CH2:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)#[N:17]
Reactant: C=CC#N
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCCn1c2ccccc2c2ccccc21
Reaction time: 1 h
Yield: 42 %

Procedure:
Carbazole (8.0 g) was suspended in 100 ml of toluene, and 4 ml of acrylonitrile and subsequently 0.5 ml of Triton B were added to the suspension, whereby the suspension was solidified. Then, the reaction mixture was allowed to stand for one hour, and methanol was added thereto, followed by filtration to give 4.41 g (42%) of the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[NH2:31][CH2:32][C:33]([N:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH2:44][O:45][C:46]2[C:54]3[N:53]=[C:52]([O:55][CH3:56])[N:51]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[C:50]=3[CH:49]=[CH:48][CH:47]=2)[C:38]=1[Cl:64])[CH3:36])=[O:34].O>CN(C=O)C>[Cl:64][C:38]1[C:39]([CH2:44][O:45][C:46]2[C:54]3[N:53]=[C:52]([O:55][CH3:56])[N:51]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[C:50]=3[CH:49]=[CH:48][CH:47]=2)=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=1[N:35]([CH3:36])[C:33](=[O:34])[CH2:32][NH:31][C:18]([CH:15]1[CH2:16][CH2:17][N:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH2:14]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(C(=O)O)C2)C1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C4CCN(C5CCN(C(=O)OC(C)(C)C)C5)C4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
A solution of 1′-(tert-butoxycarbonyl)-[1,3′-bipyrrolidine]-3-carboxylic acid (0.5 g, 1.0 mmol) in anhydrous DMF (20 ml) was treated with HOBT (Hydroxybenzotriazole) (0.21 g, 1.52 mmol), EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide), hydrochloride (0.24 g, 1.27 mmol) then 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.50 g, 1.0 mmol) and the mixture was stirred at room temperature overnight. The reaction was treated with water (100 mL) and the resulting precipitate was filtered. The aqueous mixture was treated with aqueous saturated sodium bicarbonate (100 mL), extracted with ethyl acetate (200 mL×2). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give a white solid, 0.62 g that was purified by chromatography (silica gel, dichloromethane and methanol gradient) to afford tert-butyl 3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)carbamoyl)-[1,3′-bipyrrolidine]-1′-carboxylate as a white solid, 0.41 g (53%), that was pure by LC/MS (+ESI) m/z 766 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH:10]=4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1.I[CH2:24]I.C([Zn]CC)C.[Cl-].[NH4+]>ClCCl.CCCCCC>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@:9]45[CH2:24][C@@H:10]4[CH2:11][C@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@H]1C3=CC[C@H](O)[C@@]3(C)CC[C@H]21
Reactant: ICI
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@H]3C[C@@]312
Temperature: 25 °C
Reaction time: 21 h

Procedure:
i)—A solution of (7α,17β)-3-methoxy-7-methylestra-1,3,5(10),14-tetraen-17-ol [Segaloff, A. et al, Steroids 22, 99 (1973); 25.4 g] and diiodomethane (27 ml) in dry dichloromethane (500 ml) was cooled to 0° C. A solution of diethylzinc in hexane (15% wt., 300 ml) was added in 1 h and the reaction mixture was stirred for 21 h at room temperature. Ice was added and the mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted into diethyl ether; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-trien-17-ol (6.50 g).
Reaction SMILES: Cl.[NH2:2][N:3]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]1[C:9]([O:11]C)=O.Cl.O1CCOCC1.[C:20](#[N:22])[CH3:21]>>[Cl:8][C:7]1[N:3]2[C:4]([C:9](=[O:11])[NH:22][C:20]([CH3:21])=[N:2]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Cl)n1N
Reactant: CC#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn2c(Cl)ccc2c(=O)[nH]1
Temperature: 82 °C
Yield: 64 %

Procedure:
A mixture of methyl 1-amino-5-chloro-1H-pyrrole-2-carboxylate hydrochloride (Example 13 A, 2.2 g, 9.8 mmol) and 4 N HCl in dioxane (6.0 mL, 24 mmol) in acetonitrile (90 mL) was placed in a sealed tube and heated at 82° C. overnight. The reaction mixture was concentrated and diluted with fresh acetonitrile (100 mL) and triethylamine (5 mL). The reaction mixture was heated at 85° C. overnight, concentrated to dryness and diluted with EtOAc to 150 mL. The EtOAc solution was washed with 1 N HCl, followed by saturated NaHCO3 solution and brine. The solution was dried over MgSO4 and concentrated to a solid. The solid was triturated with Et2O/hexane to give the title compound as a brown solid (1.15 g, 64%): 1H NMR (CDCl3) δ 6.99 (d, 1H, J=4.38 Hz), 6.42 (d, 1H, J=4.38 Hz), 2.40 (s, 3H); MS (ESI+) 183.98, 185.97 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)CN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC(C)C)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-4-(4-isobutylpiperazin-1-yl)-3-nitropyridin-2-amine (0.032 g, 0.10 mmol), and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.023 g, 0.17 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 40% ethyl acetate in dichloromethane, and then 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a white solid (0.013 g, 32%); 1H-NMR (500 MHz, DMSO-d6) 0.90 (d, J=6.55 Hz, 6H, CH(CH3)2), 1.83 (m, 1H, CH(CH3)2), 2.12 (d, J=7.39 Hz, 2H, N—CH2), 2.55 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.83 Hz, 2H) and 8.13 (d, J=8.78 Hz, 2H) (3,5-C6H4OMe2 and 2,6-C6H4—OMe), 8.07 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.30 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CC(O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:20]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
The mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150.0 mg, 0.34 mmol), copper(I) iodide (20.0 mg, 0.1 mmol), N,N-dimethylglycine hydrochloride (37.5 mg, 0.27 mmol), morpholine (0.78 mL, 9.0 mmol) and potassium carbonate (140.0 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL). was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (123.7 mg, 80.0%) as a white solid: MS (ESI) M+1=456.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]2)[CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:28][C:26]1[CH:25]=[N:24][N:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:27]=1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnn(C2CCN(C)CC2)c1
Yield: 52.1 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.30 g, 1.66 mmol) to afford the desired product (223 mg, 52%) as a light yellow solid. ESI MS m/z 428 [C20H22BrN5O+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(S)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Sc3cccc(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-fluoro-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-fluoro-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 351 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([N:12]([CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Cl)c1ncc(Br)cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
The 5-Bromo-pyrimidine-2-carbonyl chloride (55 g, 250 mmol) was dissolved in tetrahydrofuran (828 ml) and dimethyl-amine (2M solution in tetrahydrofuran) (373 ml, 745 mmol) was added portionwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500 ml) and washed with H2O (500 ml). The water layer was further extracted with CH2Cl2 (5×500 ml), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated in vacuo and then suspended in methyl-t-butylether (650 ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-t-butylether (100 ml) the solid was dried in a vacuum oven at 55° C. for 12 hours to afford the title compound 5-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-2: 44 g, 77%) as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:21]=1.[C:22]12([CH3:34])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]2[C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:31]([CH:23]3[CH2:24][CH:25]4[C:28]([CH3:30])([CH3:29])[C@@:22]3([CH3:34])[CH2:27][CH2:26]4)=[O:32])[C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:13])([F:14])[F:15])[C:6]=2[CH:21]=1
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Reactant: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(C(=O)N1C(=O)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc31)C2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 39.6 %

Procedure:
To a solution containing (+) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (12.97 g, 0.041 mol), 4-dimethylaminopyridine (1.02 g, 0.0083 mol), and (-) camphanic acid chloride (14.22 g, 0.06556 mol) in 350 mL of dry dichloromethane, stirred under argon in an ice bath, was added triethylamine (22.84 mL, 0.164 mol). The cooling bath was removed and the reaction was allowed to proceed at room temperature. After 75 min. the reaction was judged complete by thin layer chromatography (SiO2, 4% EtOAc in CHCl3), and the solution was diluted with 500 mL of CHCl3 then washed with 10% citric acid (2X), water (1X), and brine (1X). Drying (MgSO4), filtration, and removal of the solvent in vacuo left a colorless foam. This material was triturated with 200 mL of boiling hexane. On cooling to room temperature the desired diastereomeric camphanate imide precipitated. The solid was collected on a frit, washed with a little cold hexanes and dried in vacuo to give 7.79 g of 6-chloro-1-(1S)-camphanoyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as white crystals. mp: 164°-165° C. HPLC purity: 99.2% @254 nm. 1H-NMR (CDCl3): δ0.77 (s, 3H), 0.86-0.96 (m, 4H), 1.08 (s, 3H), 1.19 (s, 3H), 1.44 (m, 1H), 1.76 (m, 1H), 1.95 (m,1H), 2.51 (m, 2H), 7.42 (dd, J=2.4,9.0 Hz, 1H), 7.63 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 4-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDC13) δ 4.62 (2H, s), 6.68 (1H, d, JH,H=11.92), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: [CH2:1]([Zn]CC)[CH3:2].ClCI.[CH3:9][C:10]1([CH3:31])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2[CH:15]=[C:14]([C:22](=C)[CH2:23][CH2:24][OH:25])[C:13](OCCC)=[CH:12][C:11]1=2.C1(O)CC1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClC(Cl)C.C(Cl)Cl>[CH3:9][C:10]1([CH3:31])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2[CH:15]=[C:14]([C:22]3([CH2:23][CH:24]=[O:25])[CH2:2][CH2:1]3)[CH:13]=[CH:12][C:11]1=2
Reactant: C=C(CCO)c1cc2c(cc1OCCC)C(C)(C)CCC2(C)C
Reactant: CC[Zn]CC
Agent: O=[Cr](=O)([O-])Cl
Agent: ClCI
Agent: OC1CC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(C3(CC=O)CC3)ccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
In a 15 mL round-bottom flask (oven dried and under argon) was added anhydrous dichloroethane (6 mL) and diethyl zinc (0.34 mL, 3.3 mmol). The mixture was cooled to 0° C. and chloroiodomethane (0.43 mL, 6.0 mmol) was slowly added via syringe. The reaction mixture was stirred at 0° C. for 5 min. and a solution of the above homoallylic alcohol (2: R2 =H; 0.41 g, 1.57 mmol) in dichloroethane (2 mL) was slowly added. The mixture was allowed to warm to room temperature and stirred for one hour. The reaction mixture was then quenched with saturated NH4Cl and the aqueous phase was extracted with EtOAc (2×15 mL). The organic solution was washed with saturated NaCl, dried (Na2SO4) and concentrated in vacuo. Crude [1-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropyl]ethanol (3: R2 =H) was recovered in 63% yield (0.27 g) and carried directly on to the next step. To a solution of the above cyclopropyl alcohol (3: R2 =H; 0.25 g, 0.92 mmol) in 5 mL CH2Cl2 at room temperature was added PCC (0.4 g, 1.84 mmol). The reaction mixture was stirred for 3 hours and then filtered and rinsed with 15% EtOAc/hexane through a pad of celite/silica gel. Solvent was removed in vacuo to provide 230 mg of 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropaneacetaldehyde (4: R2 =H) as a white solid in 93% yield. 1H NMR (400 MHz, CDCl3) δ9.78 (t, J=2.5 Hz, 1H, aldehyde), 7.20 (d, J=8.1 Hz, 1H, aromatic), 7.18 (d, J=2.0 Hz, 1H, aromatic), 6.99 (dd, J=8.1 and 2.1 Hz, 1H, aromatic), 2.57 (d, J=2.6 Hz, 2H, CH2), 1.66 (s, 4H, 2CH2), 1.26 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3), 1.02 (dd, J=6.4, 4.7 Hz, 2H, CH2), 0.87 (dd, J=6.1,4.6 Hz, 2H, CH2).
Reaction SMILES: [CH2:1]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)N)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O>Cl>[CH3:22][C:20]1[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:11]2[C:16]([C:19]=1[C:18]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2
Reactant: Cc1ccc(N(N)CCc2ccccc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Product: CCOC(=O)c1c(C)n(CCc2ccccc2)c2ccc(C)cc12
Temperature: 110 °C
Yield: 61.1 %

Procedure:
1-phenethyl-1-p-tolylhydrazine (3.7 g, 16.3 mmol) was dissolved in ethanolic HCl (40 mL, pH of the solution was acidic) and ethyl acetoacetate (2.0 mL, 16.3 mmol) was added to it. The reaction mixture was heated at 110° C. for 1.5 h at which point the reaction was found complete by TLC and LC-MS. The reaction mixture was concentrated under reduced pressure, the residue was suspended in saturated aqueous NaHCO3 (pH 9) and extracted with ethyl acetate (100 mL×2). The organic layer was separated, dried (Na2SO4) and concentrated to obtain a crude product as dark brown oil. Purification of crude product by flash column chromatography (silica gel, 230-400 mesh, eluent: 5-10% ethyl acetate-hexanes) furnished 3.2 g of pure product as yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:15][C:16]1[C:21]([CH:22]=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:15][C:16]1[C:17]([C:2]2[C:3]([CH3:14])=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:18][CH:19]=[CH:20][C:21]=1[CH:22]=[O:23]
Reactant: Cc1nc(N2CCOCC2)ncc1Br
Reactant: O=Cc1cccc(B(O)O)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc(N2CCOCC2)ncc1-c1cccc(C=O)c1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
4-(5-Bromo-4-methylpyrimidin-2-yl)morpholine (372 mg), (2-fluoro-3-formylphenyl)boronic acid (315 mg), and potassium phosphate (918 mg) were mixed with toluene (10 ml) and water (10 ml), and palladium acetate (16 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (59 mg) were added thereto, followed by stirring at 100° C. for 4 hours. (2-Fluoro-3-formylphenyl)boronic acid (315 mg), potassium phosphate (918 mg), palladium acetate (16 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (59 mg), and water (1 ml) were added to the reaction mixture, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, CHCl3 and water were then added thereto, and the insoluble matter was removed by filtration. The organic layer of the filtrate was washed with water and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl3) to obtain 2-fluoro-3-[4-methyl-2-(morpholin-4-yl)pyrimidin-5-yl]benzaldehyde (282 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:21].O1CCOCC1>ClCCl>[ClH:1].[ClH:21].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc(Cl)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(c2cccc(Cl)c2)C1
Reaction time: 4 h

Procedure:
tert-Butyl 1-(3-chlorophenyl)pyrrolidin-3-ylcarbamate (120 mg, 0.404 mmol) in dichloromethane (0.5 ml) was treated with 4 molar hydrogen chloride in dioxane (1011 μL, 4.04 mmol) at ambient temperature in an open flask with rapid stirring. After 4 hours, the reaction was concentrated in vacuo to provide the di-hydrochloride salt of the title compound as a crude solid (122 mg, >100%).