Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:25][C:22]([F:23])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(2-trifluoromethylphenylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (0.450 g, 1.20 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.4 mL). The resulting mixture was stirred at ambient temperature for 16 hours and then quenched with saturated aqueous solution of Na2CO3 (10 mL). The organic phase was separated and washed with water (10 mL), saturated NaCl (10 mL), dried over MgSO4 and then concentrated in vacuo. The crude title compound was obtained and used without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl.[CH:29]([C:31]1([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:33][CH2:32]1)=O>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:37]([O:36][C:35]([NH:34][C:31]1([CH2:29][NH:2][C@@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:33][CH2:32]1)=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: O=CC1(NC(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](CC(C)C)NCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
Methyl D-leucinate hydrochloride (2.73 g, 15.1 mmol), zinc chloride (2.8 g, 20.5 mmol), and sodium triacetoxyborohydride (9.16 g, 41.1 mmol) were added to a dichloromethane (200 ml) solution of benzyl (1-formylcyclopropyl)carbamate (3.0 g, 13.7 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, the residue obtained was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated brine and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=2:1 (v/v)] to give the title compound (2.24 g, 47%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Oc1cccnc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncccc1O
Yield: 56 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-3-hydroxypyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 50:50, 93 mg, 56%) which was obtained as a light yellow solid. MS: m/e=377.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1)#[N:2].[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>P(CC1C2N(C=C(C(O)=O)N=2)C=CC=1)(O)(O)=O>[NH:18]1[C:1]([CH2:3][C:4]2[N:9]3[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=[C:8]3[CH:7]=[CH:6][CH:5]=2)=[N:2][N:20]=[N:19]1
Reactant: CCOC(=O)c1cn2c(CC#N)cccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: O=C(O)c1cn2cccc(CP(=O)(O)O)c2n1
Product: CCOC(=O)c1cn2c(Cc3nnn[nH]3)cccc2n1
Temperature: 25 °C

Procedure:
The title material is prepared by heating the title product of Example 99 with azido tributylstannane at 80° C. for 72 h. After cooling to room temperature, the reaction is treated with methanolic HCl for 30 min., diluted with 4N HCl, washed with diethyl ether and concentrated to yield title material.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:22](=[O:39])[CH:23]([N:25]2[CH2:30][CH2:29][C:28]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)([OH:31])[CH2:27][CH2:26]2)[CH3:24])[CH:7]=[C:8]([CH3:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([C@@H:22]([OH:39])[C@H:23]([N:25]2[CH2:30][CH2:29][C:28]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)([OH:31])[CH2:27][CH2:26]2)[CH3:24])[CH:7]=[C:8]([CH3:21])[C:9]=1[O:10][Si:11]([CH:15]([CH3:16])[CH3:17])([CH:12]([CH3:13])[CH3:14])[CH:18]([CH3:19])[CH3:20]
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(Cl)cc3)CC2)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(Cl)cc3)CC2)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
A mixture of sodium borohydride (0.054 g, 1.43 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3,5-dimethyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (0.77 g, 1.42 mmol in 25 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white solid which precipitated was collected by filtration and dried to yield 0.44 g (56%) of (1R*,2R*)-1-(3,5-dimethyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 211.5-212.5° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:13]=[N+:14]=[N-:15]>C1C=CC=CC=1>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[NH:15][N:14]=[N:13][N:11]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: [N-]=[N+]=N
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)c2nnn[nH]2)cc1

Procedure:
A mixture of p-toluenesulfonyl cyanide (0.0 g.) and excess hydrazoic acid in 50 ml. of benzene is stirred at room temperature for 20 hours. The product is filtered off, dissolved in ether, filtered through celite and evaporated to a solid which on trituration with benzene has a melting point, 133°-135° C.
Reaction SMILES: [C:1]1([C:7]([NH:10][NH:11]C(OC(C)(C)C)=O)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:31][C:32]([CH3:48])([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:33](=O)[CH2:34][C:35]([O:37]CC)=O.C(OCC)(=O)C>C(Cl)Cl.C(O)(=O)C>[CH3:48][C:32]([C:33]1[CH2:34][C:35](=[O:37])[N:10]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([CH3:9])[CH3:8])[N:11]=1)([CH3:31])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(C)(C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(Cc1ccccc1)C1=NN(C(C)(C)c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.6 %

Procedure:
tert-Butyl 2-(2-phenylpropan-2-yl)hydrazinecarboxylate (250 mg, 1.00 mmol) was dissolved in methylene chloride (2 mL), mixed with p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) and stirred at room temperature for 16 hours. After the stirring, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate to terminate the reaction and then separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (3.0 mL) and acetic acid (70 μL), and mixed with ethyl 4,4-dimethyl-3-oxo-5-phenylpentanoate (248 mg, 1.00 mmol) and stirred at 90° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and mixed with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:9 to 3:7) to give 42 mg of the desired product as a brown oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])[CH2:19][CH2:18]1>CC1C=CC=CC=1>[C:4]([CH:5]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:11]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(C)=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 4 parts of a sodium hydride dispersion 60% in 180 parts of methylbenzene are added dropwise 12 parts of ethyl 3-oxobutanoate at room temperature. Then there is added 1 part of N,N,N-tridecylmethanammonium chloride and the whole is warmed to 40° C. At this temperature, a solution of 25 parts of [1-(3-chloropropyl)-4-piperidinyl](4-fluorophenyl)methanone in 45 parts of methylbenzene is added slowly. The whole is heated to reflux and stirring is continued overnight at reflux temperature. The reaction mixture is cooled to room temperature and filtered over Hyflo. The filtrate is evaporated, yielding 24 parts of ethyl α-acetyl-4-(4-fluorobenzoyl)-1-piperidinepentanoate as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:23][CH3:24])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[Cl:22])O)[CH3:2].S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC.CO>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:23][CH3:24])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[Cl:22])[CH3:2]
Reactant: CCOC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)cc1Cl
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1Cl)OC
Temperature: 0 °C

Procedure:
A mixture of 3-(4-Benzyloxy-2-chloro-phenyl)-3-hydroxy-2-methoxy-propionic acid ethyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield a compound which was dissolved in methanol was treated with Mg (20 eq) and stirred until gas evolution was observed. Cooled to 0° C. and stirred for 4 hours. The solvent was removed and the residue reconstituted in ether washed with HCl 1N and brine and concentrated to give the title product.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Cl:20][C:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C1OC(Cl)(c2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
Over a period of 15 minutes, 22.5 parts of 2-benzoylbenzoic acid are added, in small portions, while stirring, to 40 parts of thionyl chloride. The reaction mixture is then brought slowly to reflux and this is maintained for 90 minutes. The excess thionyl chloride is removed in vacuo and the residue is taken up in 50 parts of anhydrous benzene and the whole is then evaporated to dryness in vacuo. The operation is repeated a second time and then the residue is taken up in 80 parts of anhydrous tetrahydrofuran. This solution is used in that form in the stage described below.
Reaction SMILES: Cl.Cl.[N:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=[CH:9][CH:8]=[N:7]2.CCOC1C=CC(N)=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43](O)=[O:44])[C:38]2=[O:46])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N>[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:10]4[C:11]5[N:6]([CH:5]=[CH:4][N:3]=5)[N:7]=[CH:8][CH:9]=4)=[CH:14][CH:15]=3)=[O:44])[C:38]2=[O:46])=[CH:33][CH:32]=1
Reactant: Nc1ccc(Nc2ccnn3ccnc23)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: CCOc1ccc(N)cc1
Agent: Cl
Solvent: CC#N
Product: O=C(Nc1ccc(Nc2ccnn3ccnc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.4 %

Procedure:
To a 2 dram vial was added N1-(imidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine di-HCl salt (0.080 g, 0.3 mmol) from 1c, 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.13 g, 0.57 mmol), EDCI (0.11 g, 0.57 mmol), HOBt (0.077 g, 0.57 mmol), TEA (0.16 ml, 1.1 mmol), and CH3CN (4 ml). The reaction was allowed to stir around 25° C. for 12 hrs. The solvent was then removed in vacuo and the sample was diluted with MeOH (4 ml). The solution was purified by HPLC (20-100% methanol gradient), which yielded 0.015 g of the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.96 (1H, s), 9.47 (1H, s), 8.59 (1H, dd, J=7.38, 2.29 Hz), 7.99-8.27 (3H, m), 7.67-7.85 (3H, m), 7.55-7.67 (2H, m, J=9.16, 5.09 Hz), 7.33-7.49 (3H, m), 6.66-6.82 (1H, m), 6.55 (1H, d, J=6.10 Hz) LC/MS, m/e 441 (M+1). HPLC Rt, 2.64 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3S[CH2:7][C:6]2=1.O[O:22][S:23]([O-:25])=O.[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[S:23](=[O:25])(=[O:22])[CH2:7][C:6]2=1
Reactant: COc1ccc2c(c1)c1c(n2C)-c2ccccc2SC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)c1c(n2C)-c2ccccc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene in MeOH (3 mL) and H2O (5 mL) was added OXONE (1.68 g, 2.74 mmol). The reaction mixture was stirred overnight at 25° C. The solvent was removed in vacuo and the residue was then partitioned between saturated NaHCO3 aqueous solution and CH2Cl2, the aqueous layer was extracted with CH2Cl2 and the organic layers were dried and concentrated to yield crude product. The crude product was then purified by flash chromatography to yield the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:40].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)=[O:40])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(c1cccc(CS(=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)thio)methyl)phenyl)propanoate (158 mg) in methanol (0.95 mL) was added a solution of sodium periodate (66 mg) in water (50 μL), and the mixture was stirred at room temperature for 7 hr. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (143 mg) as a colorless oil.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:1][CH2:4][C:3]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:5]
Reactant: BrBr
Reactant: COC(=O)COc1ccccc1C(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (1.2 g, 7.2 mmol) in chloroform (5 mL) was added drop wise to a solution of methyl (2-acetylphenoxy)acetate (1.5 g, 7.2 mmol) in chloroform (45 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature, diluted with EtOAc and washed with sodium bicarbonate water, brine, dried over magnesium sulfate and concentrated to give the sub-title compound as an oil which solidified (2.1 g, 100%). LCMS calc. for C11H12BrO4 (M+H)+: m/z=287.0, 289.0. found: 287.0, 289.0.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.[CH3:23][NH:24][CH:25]1[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26]1.C([BH3-])#N.[Na+]>CO.O.[Cl-].[Zn+2].[Cl-]>[CH3:23][N:24]([CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH:25]1[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC(C=O)CC2)cc1
Reactant: CNC1CCN(C)C1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC(N(C)CC2CCN(c3ccc(NC(=O)OC(C)(C)C)cc3)CC2)C1
Reaction time: 0.33 h
Yield: 101.6 %

Procedure:
To a suspension of tert-butyl [4-(4-formyl-piperidin-1-yl)-phenyl]carbamate (0.20 g, 0.66 mmol) in methanol (5 mL) is added N,N′-dimethyl-3-aminopyrrolidine (0.15 g, 1.3 mmol). The reaction mixture is stirred for 20 minutes and then a mixture of zinc chloride (53 mg) and sodium cyanoborohydride (50 mg) in methanol (2 mL) is added in a dropwise fashion. After stirring overnight at room temperature, the reaction mixture is diluted with water and extracted 3× with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl [4-(4-{[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-methyl}-piperidin-1-yl)-phenyl]-carbamate as a foam (0.27 g, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=[N:54][C:49]2C=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NCC#N>CN(C=O)C>[C:48]([CH2:49][NH:54][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=4[F:25])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=2)[C:28]=1[CH3:36])#[N:47]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NCC#N)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and aminoacetonitrile (9.3 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9.1 mg, 33%). LC-MS m/z 560 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:5][O:6][CH:7]([CH2:9][OH:10])[CH3:8])[CH3:4].[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Zr+4].C(=O)([O-])[O-].O>[C:11]([O:10][CH2:9][CH:7]([CH3:8])[O:6][CH2:5][CH:3]([O:2][CH3:1])[CH3:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC(C)COC(C)CO
Agent: [Zr+4]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(C)COC(C)COC(=O)c1ccccc1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
Dipropylene glycol monomethyl ether (444.6 grams; 3.0 mol), benzoic acid (373.7 grams; 3.06 mol), toluene (50 ml) and zirconium carbonate (2.0 grams) were placed into a 200 ml, 3-necked round bottom flask equipped with stirrer, thermometer, heating mantle, Dean Stark water trap, condenser and 10" Vigneux column. The reaction temperature was 180° C. at the beginning of the reaction and 217° C. after 6.5 hours with stirring. During that time, water (44 mls) was removed. The reaction was continued the next day for 2.5 hours at 224°-226° C. with the removal of water (56 mls.). The reaction mixture was washed at 95°-100° C. three times with sodium carbonate (15%) and then washed with water (400 ml). Then additional water (200 ml) was added and the product separated and dried at 125°, cooled to 100° C. and filtered. The desired product (694.6 grams) was obtained representing a yield of 91.8%. It assayed 99.5% with the following properties:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cnn(C)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 89.5 %

Procedure:
(S)-5-Methyl-2-(1-((5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (37 mg, 0.06 mmol) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) and a solution of ammonia (7N in methanol, 1 mL, 7 mmol) according to the method described in Example 27 to give 25 mg (85% yield) of the title compound. Purity 98%.