Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)CCCC1.P([O-])([O-])([O-])=O.[BH4-].[Na+].[C:14]([O:17][CH:18]1[CH:22]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]([C:27]([O:29][CH3:30])=[O:28])[CH:20]([OH:31])[CH2:19]1)(=[O:16])[CH3:15]>O.CO>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH:22]1[CH:18]([O:17][C:14](=[O:16])[CH3:15])[CH2:19][CH:20]([OH:31])[CH:21]1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C1C(O)CC(OC(C)=O)C1CC(=O)O
Reactant: O=C1CCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC1C(OC(C)=O)CC(O)C1C(=O)OC
Reaction time: 2 h

Procedure:
The cyclopentanone VI (8.6 g.), obtained according to the previous example, is dissolved in 50 ml. of methanol and added to 500 ml. of a phosphate buffer adjusted to a pH of 5.3. Then 20 ml. of an aqueous solution containing an excess of sodium borohydride (1.25 g.) is added at 5° C. After two hours at room temperature, 200 ml. of water is added to the reaction mixture which is then extracted several times with ethyl acetate. The combined organic layers are dried on MgSO4 and then evaporated to dryness giving 8.4 g. (98%) of crude methylester of 5-acetoxy-2-carbomethoxy-3-hydroxycyclopentaneacetic acid. This product examined by gas chromatography exhibits an 80% purity. The product which may be further purified by column chromatography has all the substituent groups with the desired orientation. The compound may not be distilled without decomposition. The principal absorption peaks in the N.M.R. spectrum in CDCl3 occur at the following frequencies expressed in δ units: 2.05 (3H, singlet), 3.65 (3H, singlet), 3.72 (3H, singlet), 4.30-4.70 (1H, multiplet, 5.18-5.43 (1H, multiplet).
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](Cl)=[N:16][O:17][CH3:18]>CCOCC>[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](=[N:16][O:17][CH3:18])[C:5]#[N:6]
Reactant: [C-]#N
Reactant: CON=C(Cl)c1ccccc1COc1cc(C)ccc1C
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Dimethyl sulfoxide (2 ml) and 95% sodium cyanide (0.21 g, 0.004 mol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl chloride (0.60 g, 0.002 mol), and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (0.45 g, 76.4%) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[Cl:22].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=4)[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(3,4-dichlorophenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 87% overall yield. FDMS m/e=419 (M+ of free base). α[D]589=−7.76 (c=0.82, methanol).
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]5[O:42][CH:3]=[CH:4][N:5]=5)[CH:10]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(OCc2ncco2)cc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 20-45_90 mins) to afford N-(1H-indazol-5-yl)-2-(3-(oxazol-2-ylmethoxy)phenyl)quinazolin-4-amine. (12 mg, 0.028 mmol).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>ClCCl.CCOCC>[Cl:24][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A mixture of 1.9 g (6.456 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and 0.515 ml (7.1 mmol) thionylchloride in 20 ml dichloromethane was stirred for 1 h at RT. The reaction mixture was taken up in ether and washed with sodium bicarbonate solution and water. The ether phase was concentrated under reduced pressure to give 1.97 g of pure 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a suspension of the 254 (26.8 mg, 0.84 mmol) in THF (1.6 mL) was added 2-phenylacetyl isothiocyanate (23 mg, 0.13 mmol). The mixture was stirred for 1 hr transferred onto a chromatography column and eluted sequentially with EtOAc/MeOH (9:1) and EtOAc/hexane (1:1), to afford title compound 255a (30 mg, 72% yield) as a white solid. 1HNMR: (DMSO-d6) δ (ppm): 12.65 (s, 1H), 12.43 (s, 1H), 11.79 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=7.6 Hz, 2H), 7.91 (m, 1H), 7.52 (m, 4H), 7.43 (m, 1H), 7.34, (m, 4H), 7.27 (m, 1H), 7.18 (m, 1H), 3.83 (s, 2H). MS (m/z): 498.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([OH:7])=O.C(Cl)CCl.[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:13][N:2]([CH3:1])[CH2:3][CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)=[O:7]
Reactant: CN(C)CC(C(=O)O)c1ccsc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CN(C)CC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-20% MeOH/CH2Cl2) gave pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide. The pure compound was taken up in CH2Cl2 and HCl was added. The solvents were evaporated to give pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>C(O)C>[CH3:19][C:17]1[N:16]=[C:15]([S:20][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:14]=[C:13]([NH2:12])[CH:18]=1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cc(N)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
In a 100 mL round bottom flask, 2-(bromomethyl)-1,3,4-trichlorobenzene (550 mg, 2.0 mmol), 4-amino-6-methylpyrimidine-2-thiol (282 mg, 2.0 mmol), and triethylamine (0.28 mL, 2.0 mmol) were mixed in ethanol (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. To the crude solid, water (50 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide a white solid (530 mg, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.65 (s, 2H), 6.03 (s, 1H), 6.90 (br, 1H), 7.55 (d, 1H), 7.64 (d, 1H); M+ 334, 336.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(C(F)(F)F)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-trifluoromethylphenylboronic acid (161 mg, 0.85 mmol) the subtitle compound was obtained (204 mg, 58%). 1H NMR (DMSO) δ 8.64(d, 1H), 8.46(dd, 1H), 8.16(d, 1H), 7.97(d, 2H), 7.92(d, 1H), 7.85–7.78(m, 3H), 7.63(d, 1H), 4.05(s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[ClH:26].O>O1CCOCC1>[Cl:26][CH2:14][CH2:13][C:12](=[O:15])[C@@H:11]1[C@:16]2([CH3:25])[C@H:8]([C@H:7]3[C@H:19]([C:18](=[O:24])[CH2:17]2)[C@:20]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCCl)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 2 h

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) was dissolved in dioxan (40 ml) and dry hydrogen chloride passed through the solution for 1 hour. The mixture was left to stand for a further 2 hours, then poured into water and the sticky solid extracted into ether. The extracts were washed with saturated sodium bicarbonate, water and then dried over anhydrous sodium sulphate. After evaporation and trituration of the resulting foam with ether/petrol the title compound (375 mg) was obtained as a white solid. m.p. 110°-112° with gas evolution [α]D + 100° (c = 1.06).
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].[Cl:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]([CH:35]([CH3:37])[CH3:36])[C:32]([SH:34])=[N:33][C:29]=2[CH:28]=1.CCN(CC)CC>>[Cl:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]([CH:35]([CH3:37])[CH3:36])[C:32]([S:34][C:2]3[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=4)([CH:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:6][C:7]=3[OH:8])=[N:33][C:29]=2[CH:28]=1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4n3C(C)C)C(=O)O2)cc1Cl
Yield: 11.1 %

Procedure:
A solution of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one (300 mg, 0.78 mmol), 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol (181 mg, 0.80 mmol) and Et3N (0.1 mL, 0.80 mmol) was stirred at 55° C. for 5 hrs. The mixture was concentrated and purified by prep HPLC to obtain 50 mg product (11% yield). 1H NMR (300 MHz, DMSO-D6) δ: 1.49-1.61 (m, 14H) 2.23-2.30 (m, 2H) 2.57-2.66 (m, 4H) 2.91-2.96 (m, 1H), 3.81 (s, 3H) 4.73-4.79 (m, 1H) 6.93 (d, J=2.07 Hz, 1H), 7.03 (d, J=8.48 Hz, 1H), 7.09 (dd, J=8.57, 2.17 Hz, 1H), 7.12-7.16 (m, 1H), 7.28 (d, J=1.88 Hz, 1H), 7.62 (d, J=8.67 Hz, 1H). ESI-MS calcd for C29H32Cl2N2O4S: 574.1. Found (M+H+): 575.0. Anal. Calcd for C29H32Cl2N2O4S: C, 60.52; H, 5.60; N, 4.87. Found: C, 60.51; H, 5.74; N, 4.58.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 81 %

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, and benzylamine in two separate reactions using acetonitrile and 90% aqueous acetonitrile, respectively, essentially as described above in example 18 except that the reaction mixtures are filtered through 2 g of silica (ethyl acetate then dichloromethane). Combine and concentrate the appropriate fractions. Purify by column chromatography on silica gel. Elute the column with a step gradient of 50% ethyl acetate in heptane to 100% ethyl acetate to give the title compound (0.350 g, 81%). mp=60–63° C. Microanalysis (C, H, N) is consistent with the final compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](=O)[CH3:10])=[C:4](Cl)[N:3]=1.[NH2:13][NH2:14]>C(Cl)Cl>[Cl:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]2[NH:13][N:14]=[C:9]([CH3:10])[C:5]=12
Reactant: CC(=O)c1c(Cl)nc(N)nc1Cl
Reactant: NN
Solvent: ClCCl
Product: Cc1n[nH]c2nc(N)nc(Cl)c12
Yield: 53.6 %

Procedure:
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone (200 mg, 0.97 mmol) was dissolved in CH2Cl2 and treated with anhydrous hydrazine (31 mg, 0.97 mmol, 1 equiv.) at r.t. overnight. The precipitate was collected by filtration, washed with CH2Cl2, dissolved in DMSO (0.5 mL), and partitioned between EtOAc (100 mL) and water (25 mL). The organic layer was dried (brine, Na2SO4) and concentrated to afford the title compound as a white solid (95 mg, 0.52 mmol, 53%).
Reaction SMILES: [I-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[C:13](#[N:15])C>>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([C:13]#[N:15])=[O:7]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CC#N
Agent: [I-]
Agent: [Na+]
Product: N#CC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
The reaction was carried out under Argon. Cuprous cyanide (6.52 g, 72.8 mmol) and anhydrous sodium iodide (20.25 g, 135 mmol) were stirred for 2 minutes in anhydrous acetonitrile (100 ml). The resulting solution was mixed with o-bromo benzoyl chloride (15.0 g, 68 mmol) whereupon an orange precipitate formed. The mixture was stirred for 30 minutes at room temperature, filtered and concentrated in vacuo. The residue was taken up in dichloromethane and the resulting precipitate was filtered off. Concentration of the filtrate under reduced pressure gave a yellow solid. Recrystallisation from 60°-80° C. b.p.t. petroleum ether afforded o-bromo benzoyl cyanide as yellow crystals (7.14 g, 50%), melting point 64° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13][C:14](=[O:16])[CH3:15])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[CH2:12])[C:10]=2[CH:11]=1.[OH:17]C1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[Na+].[Cl-]>CO.O>[CH3:1][C:2]1[C:3]([NH:13][C:14](=[O:16])[CH3:15])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:12](=[O:17])[CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: C=C1CCCc2cc(NC(C)=O)c(C)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc2c(cc1C)CC(=O)CCC2
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
In a 50 L mechanically stirred vessel, N-(3-methyl-5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (76) (710 g, 3.30 mol) was suspended in MeOH (22.5 L) and water (1.875 L). A solution of hydroxy(tosyloxy)iodobenzene (1.30 kg, 3.30 mol) in MeOH (3.50 L) was added maintaining the internal temperature below about 20° C. After completion of addition, the solution was stirred for about 15 min and then poured into saturated aqueous NaCl (35 L). The aqueous mixture was extracted with DCM (2×12 L). The combined organic layers were washed with 5 N aqueous HCl (3.50 L), dried with Na2SO4, filtered, and concentrated to afford N-(3-methyl-6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetamide (77) (520 g, 68% yield). 1H NMR (300 MHz, DMSO): δ 9.24 (s, 1H), 7.20 (s, 1H), 6.98 (s, 1H), 3.68 (s, 2H), 2.88 (m, 2H), 2.52 (m, 2H), 2.16 (s, 3H), 2.04 (s, 3H), 1.82 (m, 2H).
Reaction SMILES: [CH:1]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]#[CH:15])[CH3:12].C(N(CC)CC)C>C(OCC)C>[CH2:11]([O:13][CH:14]1[C:1]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:9])[CH2:15]1)[CH3:12]
Reactant: C#COCC
Reactant: O=C(Cl)C1CCCCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC1CC(=O)C12CCCCCC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.1 %

Procedure:
A solution of cycloheptyl carbonyl chloride (10.0 g, 0.062 mol) and ethoxyacetylene (40% w/w solution in hexanes, 6.0 g, 0.083 mol, 12 ml) in diethylether (50 ml) was treated dropwise with triethylamine (20 ml, 0.14 mol) and the reaction stirred for 5 d at room temperature. Filtration and concentration of the filtrate in vacuo followed by chromatography (SiO2, 5:1 EtOAc:hexanes) gave the title compound as a pale yellow oil (10.5 g, 0.054 mol, 87%). δH (CDCl3, 300K) 4.78 (1H, s), 4.20 (2H, q J 7.1 Hz), 1.94-1.87 (2H, m), 1.83-1.77 (2H, m), 1.71-1.66 (2H, m), 1.63-1.52 (6H, m), 1.45 (3H, t J 7.1 Hz); m/z (ES+, 70V) 194.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[N:3]=1.[NH2:12][NH2:13]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][NH2:13])=[O:7])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: NN
Solvent: CCO
Product: Cc1nc(Cl)ccc1C(=O)NN
Temperature: 80 °C

Procedure:
6-Chloro-2-methylnicotinic acid (Example 425, Step 1) (480 mg, 2.59 mmol) was taken up in ethanol (5.2 ml). Hydrazine (0.8 ml, 12.93 mmol) was added and the reaction was heated to 80° C. overnight. It was then concentrated under reduced pressure and purified via silica gel chromatography (0-3% methanol in ethyl acetate) to yield the title compound.
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[Mg].[CH3:5][N:6]([CH3:11])[CH2:7][CH2:8][CH2:9]Cl>O1CCCC1>[CH3:5][N:6]([CH3:11])[CH2:7][CH2:8][CH2:9][Zn:2][CH2:9][CH2:8][CH2:7][N:6]([CH3:11])[CH3:5]
Reactant: CN(C)CCCCl
Reactant: [Zn+2]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)CCC[Zn]CCCN(C)C
Temperature: 70 °C

Procedure:
A solution of 38.2 g (0.28 mol) of zinc chloride in 100 ml of tetrahydrofuran is added dropwise at room temperature to a Grignard reagent prepared from 24.3 g (1.0 mol) of magnesium and 102.1 g (0.84 mol) of 3-di-methylaminopropyl chloride in 500 ml of tetrahydrofuran, and the mixture is then heated at 70° C. for 2 hours. After cooling, insoluble material is separated off by filtration, the solvent is removed and the residue is distilled in vacuo. Bis(3-dimethylaminopropyl)zinc is obtained as a crystalline solid having a melting point of 40° C. and a boiling point of 68° C./0.1 mbar.
Reaction SMILES: [CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2.CCN(C(C)C)C(C)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>C(#N)C>[CH3:36][O:37][CH2:38][C:39]([NH:26][CH:2]([CH3:1])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2)=[O:40]
Reactant: COCC(=O)Cl
Reactant: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NC(C)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
1-Methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine (118a, 14 mg, 0.041 mmol), DIPEA (12 ul, 0.070 mmol) and acetonitrile (2 ml) were charged in a 7 ml vial. Methoxyacetyl chloride (12 ul, 0.13 mmol) was added, the vial was sealed and the solution stirred (magnetic bar) at r.t. for 1 h. Concentration and purification on C18 (Kromasil) with acetonitrile:water:TFA, 45:55:0.1 to 90:10:0.1 over 30 min, afforded 5 mg (29%) of 2-methoxy-N-[1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethyl]acetamide.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13]2>C(N(CC)CC)C.C1(C)C=CC=CC=1>[O:21]=[C:11]1[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]([CH2:7][O:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])=[C:17]2[N:12]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][S:18][C:16]=12
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reaction time: 2 h

Procedure:
A few drops of triethylamine and three 0.24 ml portions of ethyl isocyanate were added to a suspension of 1.02 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one in 11.5 ml of toluene, whereby the mixture was stirred at 85° for about 2 hours between each of the additions. After the reaction was finished, the mixture is evaporated in vacuo. By recrystallization of the residue from ethanol, there was obtained pure (4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)methyl-ethylcarbamate of m.p. 136°-137°.