Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@H]2CNC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C1NC[C@H](c2cccc(O)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
A solution of (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)-imidazolidin-2-one (99 mg, 0.25 mmol) in CH2Cl2 (2 mL) is cooled to −78° C. when BBr3 (1 mmol, 1 mL of 1M solution in CH2Cl2) is added drop wise. After the addition, the mixture is warmed to 0° C. and stirred for 1 h when MeOH (0.5 mL) is added into the mixture to quench the reaction. The reaction mixture is then treated with water (3 mL) and extracted with EtOAc (3×5 mL). The combined organic layers are concentrated and purified by flash column chromatography (silica gel, 0-100% EtOAc/hexane) to provide the titled compound as a white solid (84 mg, 88%). HPLC-MS calculated for C21H17ClN2O3 (M+H+) 381.1, found 381.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH:37]=O)[CH3:32].C([BH3-])#N.[Na+]>C(O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:37][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:7][CH2:8]1)[CH3:32]
Reactant: N#Cc1ccc(NC2CCNCC2)nc1
Reactant: CCOc1cc(C=O)ccc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3ccc(C#N)cn3)CC2)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of 6-(piperidin-4-ylamino)-nicotinonitrile dihydrochloride (41.3 mg, 0.15 mmol, 1.0 equiv; intermediate B2) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate E10, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 20.5 mg (39%) of the title compound. MS (ISP): 350.7 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: NCCCc1ccccc1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Azidobenzoic acid (855 mg, 5.14 mmol), HOBt (701 mg, 5.14 mmol, 1.0 eq.) and 3-phenylpropylamine (0.969 ml, 6.68 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.21 g, 6.16 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Si:22](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:22]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Yield: 99 %

Procedure:
The reactant ethyl 4-hydroxycyclohexanecarboxylate (5.4 g, 30.73 mmol) in DCM (100 mL) was treated with DIPEA (16.06 mL, 92.2 mmol), DMAP (4.13 g, 30.80 mmol) and TBDPS-Cl (11.8 mL, 46.1 mmol) at RT for 16 h. After concentrated in vacuum, the residue was purified by CombiFlash on silica gel column using EtOAC/Hexane as eluents to give ethyl 4-(tert-butyldiphenylsilyloxy)cyclohexanecarboxylate 157a, 12.6 g, 99% yield.
Reaction SMILES: C(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9](O)=[N:10][CH:11]=1>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:3][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
75 g of phosgene are introduced at a temperature of 85°-95° C. over 1 hour into a mixture of 87.5 g of 5-chloro-2-hydroxy-3-nitropyridine in 500 ml of toluene and 3 ml of N,N-dimethylformamide. The reaction mixture is kept for 2 hours under reflux at 85°-95° C. and then allowed to cool to room temperature over a period of 18 hours. The reaction mixture is washed 3 times with water and the organic phase is dried over sodium sulfate and thereafter concentrated by evaporation. The crude product, obtained in the form of a brown oil, is crystallised from 200 ml of n-hexane, giving 67.5 g of 2,5-dichloro-3-nitropyridine (70% of theory) with a melting point of 38°-39° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12](O)=[O:13])=[C:9]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:51][O:52][C:53](=[O:56])[CH2:54][NH2:55].N1C(C)=CC(C)=CC=1C>CN(C)C=O>[CH3:51][O:52][C:53](=[O:56])[CH2:54][NH:55][C:12]([C:10]1[S:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:13]
Reactant: COC(=O)CN
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(-c3ccccc3)sc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)CNC(=O)c1sc(-c2ccccc2)cc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a mixture of 5-phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carboxylic acid (prepared according to example 2) (50 mg, 0.134 mmol) in anhydrous dimethylformamide (1.4 ml) were added HATU 152 mg, 0.402 mmol), glycine methyl ester hydrochloride (20 mg, 0.161 mmol) followed by collidine (124 μl, 0.938 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and pre-absorbed on SiO2. Purification chromatography (hexane to hexane:ethyl acetate; 6:4 to dichloromethane:methanol; 95:5) gave 47 mg of a mixture of {[5-Phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carbonyl]-amino}-acetic acid methyl ester and collidine. 1H NMR (CDCl3, 400 MHz) 7.76-7.73 (m, 2H), 7.61 (s, 1H), 7.57-7.54 (m, 2H), 7.42-7.36 (m, 3H), 7.24-7.22 (m, 2H), 6.19-6.17 (m, 1H), 4.14-4.12 (m, 2H), 3.79 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[Br:31][CH2:32][CH2:33][CH2:34][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14][C:15]=2[NH2:24]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1

Procedure:
The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate (3.7 g) and 1,3-dibromopropane (2.85 ml) were added to dimethylformamide (5 ml), and the same manner to Example 2-13 step (i) was conducted to give the titled compound as a white solid. Yield: 1.0 g (50%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=O)=[CH:9][C:8]([I:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15](OC)(OC)OC.C(O)(=O)C.[NH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[I:14][C:8]1[CH:9]=[C:10]2[C:2](=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=1)[N:1]=[CH:15][N:26]([C:27]1[CH:28]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:37])[C:11]2=[O:13]
Reactant: Nc1c(C(=O)O)cc(I)cc1C(=O)O
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C)c(-n2cnc3c(C(=O)O)cc(I)cc3c2=O)c1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
To a suspension 2-amino-5-iodoisophthalic acid (30.4 g) and in toluene (300 ml) was added trimethyl orthoformate (60 ml) followed by acetic acid (5.6 ml). The reaction mixture was stirred at 100° C. for 4 hours when additional trimethyl orthoformate (30 ml) and acetic acid (5.6 ml) was added and the heating continued for a further 21 hours. Methyl 3-amino-4-methylbenzoate (10.9 g) was added and the reaction mixture stirred at 100° C. for 21 hours. The reaction mixture was cooled to room temperature and the resultant solid collected by filtration, washed MeOH and dried in vacuo for 18 hours to yield 6-iodo-3-[5-(methoxycarbonyl)-2-methylphenyl]-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid as a white solid (21.1 g); NMR Spectrum: (DMSOd6) 2.20 (s, 3H), 3.85 (s, 3H), 7.61 (d, 1H), 8.02 (m, 1H), 8.08 (s, 1H), 8.54 (m, 1H), 8.62 (m, 2H); Mass Spectrum: M+H+ 465.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=[O:10].[Cl-].C(OC([NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([N:33]2[CH2:41][C:40]3[C:35](=[CH:36]C=[C:38](CO)[CH:39]=3)[CH2:34]2)=[O:32])[CH2:27][CH2:26]1)=O)C1C=CC=CC=1>O>[O:10]1[CH2:5][CH2:4][N:3]([CH2:6][C:7]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[CH2:41][N:33]([C:31]([C@H:28]2[CH2:27][CH2:26][C@H:25]([NH2:24])[CH2:30][CH2:29]2)=[O:32])[CH2:34]3)[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: O=C(N[C@H]1CC[C@H](C(=O)N2Cc3ccc(CO)cc3C2)CC1)OCc1ccccc1
Agent: [Cl-]
Solvent: O
Product: N[C@H]1CC[C@H](C(=O)N2Cc3ccc(CN4CCOCC4)cc3C2)CC1

Procedure:
0.15 ml of triethylamine and 0.07 ml of methanesulfonyl chloride were added to 10 ml of a tetrahydrofuranmethylene chloride suspension containing 0.31 g of N-benzyloxycarbonyl-trans-4-[(5-hydroxylmethyl-2-isoindolinyl)carbonyl]cyclohexylamine under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After the extract was dried over sodium sulfate, the solvent was removed under reduced pressure. To the residue were added 5 ml of dimethylformamide and 0.25 ml of morpholine, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform-methanol=100:1). This compound was treated with palladium-carbon under hydrogen atmosphere to obtain trans-4-[(5-morpholinomethyl-2-isoindolinyl)carbonyl]cyclohexylamine (Reference Example 13-24 in Table 8).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH:22]=O)[CH:7]=1)[CH3:2].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Reactant: NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CNCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzylamine.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(C(C)=O)C>[CH2:7]([O:6][C:4]([C:3]1[N:10]=[C:11]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=[CH:20][N:21]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)c1cccnc1N
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn2cccc(C(=O)OCC)c2n1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
A mixture of ethyl bromopyruvate (2.3 g, 10.2 m mol and ethyl 2-aminonicotinate (1.7 g, 10 m mol) in methyl ethyl ketone (17 ml) was refluxed for 5 hours. After completion of the reaction, the mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent. The residue to which saturated sodium hydrogen carbonate aqueous solution (50 ml) was added was extracted with chloroform (100 ml×3). The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate) to give the object compound (0.7 g, yield 26.7%) as crystals. m.p. 97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][O:12][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC1(C#CCO)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1(C#CCOCc2ccc3ccccc3c2)CCOCC1

Procedure:
4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran (1.2 g, 6.97 mmol) was treated with sodium hydride in THF (18 mL). After gas evolution ceased, a solution of 2-(bromomethyl)napthalene (1.70 g, 7.67 mmol) in dry DMF (9 mL) was added. After 3 hours at ambient temperature the reaction was quenched with saturated aqueous ammonium chloride. The resulting two-phase mixture was extracted with ether (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography on silica gel (100 g, 10% ethyl acetate: hexanes) provided the title compound. (2.00 g, 92%) as a colorless oil. 1H NMR (300 MHz, CDCl3); 7.80-7.90 (4H, m), 7.47-7.52 (3H, m), 4.70 (2H, s), 4.32 (2H, s), 3.87 (2H, dd, J=12,4.5 Hz), 3.67 (2H, dd, J=12,3 Hz), 3.40 (3H, s), 1.95 (2H, br d, J=13 Hz), 1.49 (2H, ddd, J=13,9,4.5 Hz); MS (M+NH4)+ =328. Analysis calc'd for C20H22O3 : C, 77.39; H, 7.14; Found: C, 76.10; H, 7.10.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:15]([Cl:16])=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[NH2:18][C@H:19]([C@@H:23]([OH:25])[CH3:24])[C:20]([OH:22])=[O:21].O>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:15]1[C:8]([Cl:7])=[C:9]([C:10]#[N:11])[CH:12]=[CH:13][C:14]=1[NH:18][C@H:19]([C@@H:23]([OH:25])[CH3:24])[C:20]([OH:22])=[O:21]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)O
Temperature: 75 °C
Reaction time: 16.5 h
Yield: 32.4 %

Procedure:
A 500 mL round bottomed flask was charged with diisopropylamine (11.81 mL, 83.60 mmol) and dry THF (100 mL) then the flask was cooled to −5° C. A 2.5 M hexane solution of n-butyllithium (30.87 mL, 77.17 mmol) was then added and the mixture was stirred for 1 h at 0° C. This pre-formed LDA solution was then added via cannula to a −78° C. solution of 2-chloro-4-fluorobenzonitrile (10 g, 64.31 mmol) in THF (100 mL) and the mixture was stirred for 2 h. To this was added a solution of hexachloroethane (16 g, 67.58 mmol) in dry THF (50 mL), and the mixture was allowed to warm to room temperature and stirred for 17 h before being concentrated to furnish a yellow solid (12.15 g) which was used directly in the next step without further purification. K2CO3 (17.8 g, 128.62 mol) was added to a solution of 2,3-dichloro-4-fluorobenzonitrile (12.15 g, 64.31 mol) and (2R,3S)-2-amino-3-hydroxybutanoic acid (11.43 g, 0.096 mol) in DMSO (150 mL) at room temperature. The reaction mixture was heated to 75° C. and stirred for 16.5 h, then was allowed to cool to room temperature whereupon water (150 mL) and ethyl acetate (150 mL) was added to the mixture which was then partitioned. The aqueous phase was then washed with EtOAc (70 mL) and the acidified with citric acid monohydrate (19 g). The aqueous phase was then extracted with EtOAc (180 mL) (×2) and the combined organics were washed with water (80 mL), dried (Na2SO4), filtered and concentrated to furnish the title compound as a brown solid (9 g, 48%). 1H NMR (500 MHz, acetone d6, δ in ppm) 7.61 (d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 6.02 (d, J=7 Hz, 1H), 4.60-4.57 (m, 1H), 4.39-4.37 (m, 1H) and 1.38 (d, J=7 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:22])[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C([O-])(=O)C>N1C=CC=CC=1>[C:23]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:22])[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@]12O
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@]32O)C1

Procedure:
3β,14β-Dihydroxyandrostan-17-one (70 mg.) was dissolved in 5 ml. of pyridine and treated with 1 ml. of acetic anhydride at room temperature for 15 hours. After evaporation of solvents, the residue was crystallized from ether to give 70 mg. of the acetate, m.p. 182°-184°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1.C(O)(=O)C.[CH2:32]1[C:35]2([CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:34][O:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCCl>[CH2:32]1[C:35]2([CH2:40][CH2:39][CH2:38][N:37]([CH2:8][C:7]3[C:2]([Cl:1])=[C:3]([NH:12][C:13]4[N:18]=[C:17]([NH:19][CH:20]5[CH2:21][CH2:22]5)[C:16]5=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]5[N:14]=4)[CH:4]=[C:5]([C:10]#[N:11])[CH:6]=3)[CH2:36]2)[CH2:34][O:33]1
Reactant: C1CNCC2(C1)COC2
Reactant: N#Cc1cc(C=O)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#Cc1cc(CN2CCCC3(COC3)C2)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 400) (20 mg, 0.053 mmol), acetic acid (9.07 tli, 0.158 mmol) and 2-oxa-6-azaspiro[3.5]nonane (16.79 mg, 0.132 mmol) in THF (0.5 ml) was stirred at room temperature to for 5 min. to achieve solution. DCE (0.5 mL) was added and after 25 min, sodium triacetoxyborohydride (33.6 mg, 0.158 mmol) was added. LCMS analysis found the desired mass of the product. The mixture was stirred overnight. The reaction mixture was then quenched with saturated aqueous NaHCO3 and stirred for 10 minutes. It was dried with a stream of nitrogen and then dissolved in DMF (1.5 mL) and purified by reverse-phase preparative LCMS.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.C([O-])(=O)C.[NH4+].[CH:21]([NH2:23])=O>O>[N:1]1[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[C:11](=[O:13])[NH:23][CH:21]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: NC=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=c1[nH]cnc2sc3c(c12)CCCC3
Temperature: 140 °C
Yield: 82.9 %

Procedure:
A mixture of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.7 g, 3.1 mmole), ammonium acetate (0.31 g, 4.04 mmole) and formamide (0.67 ml, 16.8 mmole), was stirred under reflux at 140° C. for 13 hours. It was then cooled, diluted with water (20 ml), extracted with ethyl acetate (3×35 ml), dried, concentrated and purified by column chromatography to obtain the pure 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A09) (0.53 gm, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][C:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:3]4/[C:2](=[O:10])[NH:1][C:9]5[C:4]/4=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1
Reactant: O=Cc1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Yield: 82.8 %

Procedure:
The title compound (30 mg, 83%) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using indolin-2-one (13.3 mg, 0.1 mmol) and 3-(pyridin-3-ylethynyl)-1H-indazole-6-carbaldehyde (24.7 mg, 0.1 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H), 10.64 (s, 1H), 8.90 (s, 1H), 9.64 (d, J=4.4 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.60-7.50 (m, 3H), 7.24 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H) 6.84 (t, J=7.8 Hz, 1H); MS ESI 363.1 [M+H]+, calcd for [C23H14N4O+H]+ 363.1.
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]O)(=[O:8])[CH3:7]>C(Cl)Cl.CCOC(C)=O.CO>[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][Cl:5])(=[O:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(CO)c1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (0.15 ml) was added to a stirred solution of 3-acetylaminobenzylalcohol (260 mg) and TEA (0.26 ml) in DCM (2 ml) at 0° C. The reaction was allowed to warm to room temperature and stirred for two hours. The mixture was diluted with EtOAc (20 mL) and MeOH (1 ml) and stirred for 5 minutes. The mixture was then washed with water (30 ml), organic layer was dried over sodium sulphate and solvent evaporated. The residue was columned on silica gel using DCM then ethyl acetate as eluant to give 3-acetylaminobenzylchloride (210 mg). 1H NMR (CDCl3) δ: 7.59 (s, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 7.14 (d, 1H), 4.56 (s, 2H), 2.18 (s, 3H).