Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(C=O)cc(-c2cccs2)c1OC
Yield: 91 %

Procedure:
Ex-1D: A solution of 5-bromo-3,4-dimethoxybenzaldehyde (10.23 g, 41.7 mmol) in 359 mL of ethylene glycol dimethyl ether was purged with nitrogen gas for 30 min. The solution was treated with tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol), thiophene-2-boronic acid (8.01 g, 62.6 mmol), and a solution of 2 N sodium carbonate 72 mL, 3.45 mmol). The reaction was refluxed for 16 h. The reaction mixture was concentrated, diluted with an aqueous solution of saturated sodium bicarbonate (75 mL), and extracted with dichloromethane (2×100 mL). The organic layer was dried over sodium sulfate and concentrated to a brown solid. The crude material was purified by silica gel chromatography (1:1 ethyl acetate/hexanes) to give 9.42 g (90%) of the desired 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde product. 1H-NMR (300 MHz, CDCl3) δ 9.94 (s, 1H), 7.79 (d, 1H), 7.57 (dd, 1H), 7.41 (d, 1H), 7.36 (d, 1H), 7.13 (dd, 1H), 3.97 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)[N:9]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:11]=[C:10]([N:19]2[CH2:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH2:24]2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(N)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
tert-Butyl N-[1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-4-piperidyl]carbamate (1.30 g, 2.77 mmol) was dissolved in methanol (10 mL). 4M Hydrochloric acid in dioxane (10 mL) was added. The reaction was stirred at RT for 3 hours. Saturated aqueous sodium bicarbonate was added until pH7 was reached and the organic solvents were removed in vacuo. Water (20 mL) was added and the product was extracted into ethyl acetate (50 mL). The aqueous layer was extracted with a second portion of ethyl acetate (25 mL). The combined organics were evaporated to give the desired material as a yellow foam (1.05 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].[C:10]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>O1CCCC1.C(OCC)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C@H:23]([OH:24])[C@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[NH:17][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:2]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.45 g zinc powder are suspended in 30 ml tetrahydrofuran and heated to reflux temperature. 4.4 g ethylbromodifluoroacetate are added at once and as soon as a vigorous reaction is initiated 2 g of N--BOC--L--leucinal dissolved in 5 ml tetrahydrofuran are added dropwise. After 30 minutes the reaction mixture is allowed to cool, then taken up in ethyl acetate and washed with 2N tartaric acid. The organic phase is dried over magnesium sulfate, evaporated to dryness and chromatographed over silicagel using ether/hexane 2:8 as an eluent. N--BOC--(4S,3R)-2,2-difluorostatine ethyl ester is obtained ([α]D20 =-12.2°, c=0.29 in ethanol).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[O:22])[C:20]#[N:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26].C(N(CC)CC)C>C(O)(=O)C.[Pd].ClCCl>[Cl:23][CH2:24][C:25]([NH:21][CH2:20][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:22])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2c(C(=O)C#N)cn(CC3CCCCC3)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cccc2c(C(=O)CNC(=O)CCl)cn(CC3CCCCC3)c12
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxoacetonitrile (prepared as described in Example 28; 2.39 g, 8.06 mmol) in acetic acid (50 ml) under nitrogen was added 10% palladium on charcoal (240 mg). The reaction was placed under a hydrogen atmosphere and stirred overnight. The reaction mixture was then filtered through a pad of dicalite. The dicalite was washed with acetic acid and the combined filtrate evaporated to leave a red oil. The red oil was taken up in dichloromethane (50 ml) and to this was added chloroacetyl chloride (0.77 ml, 9.67 mmol) followed by triethylamine (3.4 ml, 24.2 mmol) dropwise. The reaction was stirred for 30 minutes and poured into a separating funnel. The organics were washed sequentially with 5% aqueous sodium carbonate (2×30 ml) and brine (30 ml). The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to leave a red/brown oil. The oil was purified by flash chromatography using 20-100% (v/v) dichloromethane in heptane followed by 25-50% (v/v) diethyl ether in heptane to afford 2-chloro-N-[2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]-acetamide (2.32 g, 6.1 mmol).
Reaction SMILES: C[NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[S:3]([O:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:5])(=[O:4])[NH2:2]
Reactant: CNS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.3 %

Procedure:
To a stirred solution of 45.0 g (0.347 mole) of methylsulfamoyl chloride prepared above in 100 ml of methylene chloride was added in a thin stream a solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis, Inc., Windham, N.H. 03087) in 30 ml (0.369 mole) of pyridine and 100 ml of methylene chloride and the reaction mixture was stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a brown viscous residue. The residue was partitioned between water and ethyl ether (400 ml each). The organic layer was washed twice with 300 ml portions of water, dried over magnesium sulfate (MgSO4) and the solvent evaporated under reduced pressure to yield a solid residue. The solid was triturated with 100 ml of isopropyl ether and the solid was recollected by filtration. The solid was recrystallized from isopropyl ether to give 12.9 g (34%) of title compound as a white solid, m.p. 101°-104° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:12](SC3N(C)N=NN=3)[CH2:13][S:14][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:45]=CC=C[CH:41]=1.C(/[Sn](CCCC)(CCCC)CCCC)=C/C.O>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[C:1]([O:5][C:6]([CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:23])=[C:12](/[CH:41]=[CH:40]\[CH3:45])[CH2:13][S:14][C@H:9]12)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1nnnc1SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(C(=O)OC(C)(C)C)[C@H]2SC1
Agent: [Pd]
Agent: C/C=C\[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(C(=O)OC(C)(C)C)[C@H]2SC1
Yield: 139.8 %

Procedure:
A mixture of diphenylmethyl 7-t-butoxycarbonyl-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thio]-3-cephem-4-carboxylate (IId, 0.125 g, 0.000215 mole), bis(dibenzylideneacetone)palladium (0.0062 g, 0.00001075 mole), triphenyl phosphine (0.0084 g, 0.000032 mole), zinc chloride (0.0586 g, 0.00043 mole) and Z-1-propenyltributyl stannane (0.071 g, 0.000215 mole) in dry tetrahydrofuran (2 mL) was refluxed under argon atmosphere for 20 h. After no further conversion of starting compound IId took place, water and ethyl acetate were added. The organic phase was separated, dried and concentrated. The crude product dissolved in acetonitrile and the acetonitrile solution was washed three times with equal volumes of pentane. Flash chromatography with 20% ethyl acetate in hexane gave the title product (0.022 g, 20%) as a foam. Also recovered was 0.0435g (34.8%) of starting compound IId.
Reaction SMILES: S(=O)(=O)(O)O.C([O:14][CH:15]([CH3:39])[CH2:16][NH:17][C:18]1[C:19]([S:37][CH3:38])=[N:20][N:21]2[C:26]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[O:35][CH3:36])=[CH:25][CH:24]=[CH:23][C:22]=12)(=O)C1C=CC=CC=1.[BH4-].[Na+].[OH-].[Na+].O1[CH2:48][CH2:47][CH2:46][CH2:45]1>CO>[CH:47]1([CH2:48][CH:16]([NH:17][C:18]2[C:19]([S:37][CH3:38])=[N:20][N:21]3[C:26]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=4[O:35][CH3:36])=[CH:25][CH:24]=[CH:23][C:22]=23)[CH:15]([OH:14])[CH3:39])[CH2:45][CH2:46]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC(C)OC(=O)c3ccccc3)c(SC)nn12
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(CC3CC3)C(C)O)c(SC)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropanecarboxyaldehyde (0.047 mL) and 3 M sulfuric acid (0.21 mL) were added to a solution of 2-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-1-methylethyl benzoate (100 mg) in tetrahydrofuran (0.7 mL) while cooling on ice, and then sodium borohydride (16 mg) was slowly added thereto at the same temperature. The mixture was stirred for 30 minutes at room temperature, and then 5 N aqueous sodium hydroxide (0.3 mL) was added while cooling on ice to make the reaction mixture basic. Methanol (2.1 mL) was added to the reaction mixture, and after heating to reflux for 1 hour, it was returned to room temperature, extraction was performed with ethyl acetate, and the extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to obtain the title compound (80 mg) as a yellow oil.
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.Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>>[CH:10]1[C:11]2[N:12]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: N#CCCCn1c2ccccc2c2ccccc21

Procedure:
Carbazole (10 g, 0.060 mol) was reacted with 4-bromobutyronitrile (11.9 ml, 0.12 mol) by working in a similar manner to Example 1a).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)=[C:5]([F:21])[CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][OH:31])=[CH:4][C:5]=2[F:21])=[CH:11][C:12]=1[C:17]([F:20])([F:18])[F:19]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl 4-ethenyl-2-fluorophenyl ether (4.0 g, 12.63 mmol) in THF (13 mL) was added dropwise 9-BBN (50.5 mL, 25.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for overnight, then mixed with NaOH (25.3 mL, 76 mmol) and H2O2 (7.74 mL, 76 mmol). The mixture was stirred at 55° C. for 4 h, quenched by Na2SO3, and extracted with EA (100 mL×3). Organic phases were collected, combined, dried with anhydrous Na2SO4, and concentrated to provide the title compound (4.02 g, 95% yield). LCMS: rt=4.6 min, [M+H+]=334
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.[C@@H:23]([NH2:27])([CH2:25][CH3:26])[CH3:24].C(O)=O.C(=O)(O)[O-]>CN(C=O)C>[C@@H:23]([NH:27][C:12]1[N:11]=[C:10]([NH:9][C@@H:4]2[CH2:5][CH2:6][C@@H:7]([CH3:8])[C@H:2]([OH:1])[CH2:3]2)[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1)([CH2:25][CH3:26])[CH3:24]
Reactant: CC[C@H](C)N
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C(N)=O)C[C@H]1O
Agent: O=C([O-])O
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC[C@H](C)Nc1ncc(C(N)=O)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 90 °C
Yield: 66 %

Procedure:
To a stirring suspension of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.2 g, 0.609 mmol) in DMF (3 mL) was added (S)-(+)-sec-butylamine (0.305 mL, 3.05 mmol) and the reaction was heated to 90° C. overnight. The crude reaction mixture was concentrated under reduced pressure and then purified using reverse-phased semi-preparative HPLC (5-75% methanol+0.1% formic acid in water+0.1% formic acid, over 26 min). Fractions containing product were concentrated under reduced pressure and the resulting residue was redissolved in methanol (5 mL), passed over a Varian StratoSpheres HCO3 resin SPE tube for formic acid removal (0.9 mmol bicarbonate equiv.), and then concentrated under reduced pressure to afford 2-((S)-sec-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxamide (0.129 g, 0.402 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-1.24 (m, 15H) 1.35-1.45 (m, 1H) 1.54 (br. s., 1H) 1.66 (d, J=12.89 Hz, 1H) 1.92 (br. s., 1H) 2.14 (br. s., 1H) 2.97 (br. s., 1H) 3.71-3.99 (m, 1H) 4.55 (d, J=5.86 Hz, 1H) 6.96 (br. s., 1H) 8.34 (s, 1H) 8.90 (br. s., 1H); MS (ESI) m/z 322.5 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:41]=[CH:40][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:40][CH:41]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(OC2CCN(c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)CC2)nc(-c2ccncn2)cc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(OC2CCN(c3ccc(CN4CCNCC4)cc3)CC2)nc(-c2ccncn2)cc1=O
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of tert-butyl 4-{4-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]benzyl}piperazine-1-carboxylate (470 mg, 0.83 mmol) in dichloromethane (4.2 ml) was added trifluoroacetic acid (3.9 g, 34 mmol) at room temperature. The mixture was stirred overnight. After concentration under reduced pressure, the residue was dissolved into water. The aqueous solution was washed with ethyl acetate and basified with potassium carbonate. Extraction with chloroform was performed three times and the organic layer was dried over sodium sulfate, concentrated in vacuo to afford 1-methyl-2-[1-(4-piperazin-1-ylmethyl-phenyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one as a pale yellow solid (260 mg, 0.56 mmol, 67%).
Reaction SMILES: [CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:17][CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1ccc(C2CCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of tert-butyl 4-cyclopentylbenzoate (350 mg, 1.42 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). After stirring at room temperature for 0.5 hour, the mixture was concentrated to give 4-cyclopentylbenzoic acid (200 mg, 74%) as a white solid. LRMS (M+H+) m/z: calcd 190.10. found 190. 1H NMR (300 MHz, CD3OD): δ 12.78 (br, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 3.10-3.01 (m, 1H), 2.05-2.01 (m, 2H), 1.78-1.65 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]([CH2:14][C:15]#[CH:16])[C:7]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][C:29](I)=[CH:28][C:25]=1[C:26]#[N:27]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:25]1[CH:28]=[C:29]([C:16]#[C:15][CH2:14][N:6]([CH2:5][C:4]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:3]=2[O:2][CH3:1])[C:7]([C:9]2[NH:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH:30]=[CH:31][C:24]=1[F:23])#[N:27]
Reactant: C#CCN(Cc1ccc(OC)cc1OC)C(=O)c1ccc[nH]1
Reactant: N#Cc1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(CC#Cc2ccc(F)c(C#N)c2)C(=O)c2ccc[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of A1 (1 eq) in a mixture of DMF and Et3N (1:1) was added 2-fluoro-5-iodobenzonitrile (2 eq), CuI (0.2 eq) and Pd(PPh3)4 (0.05 eq). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with 0.1N HCl (2×) and then with brine; dried (Na2SO4) and concentrated. The resulting crude was purified by on silica gel eluting with EtOAc/petrol ether to obtain the desired compound. MS (ES) C24H20FN3O3 requires: 417, found: 418 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 11.59 (1H, bs), 7.93 (1H, dd, J=6.3, 2.0 Hz), 7.78-7.73 (1H, m), 7.53 (1H, t, J=9.1 Hz), 7.13 (1H, d, J=8.3 Hz), 6.93 (1H, s), 6.60 (1H, d, J=2.3 Hz), 6.53 (1H, dd, J=8.3, 2.3 Hz), 6.50-6.38 (1H, m), 6.10 (1H, s), 4.77 (2H, s), 4.50 (2H, s), 3.78 (3H, s), 3.76 (3H, s).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=O)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.CSC.[ClH:28]>O1CCCC1.C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH2:23])=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[ClH:28]
Reactant: CC(C)c1ccc(S(=O)(=O)Cc2ccc(CC(N)=O)cc2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Solvent: CCO
Product: CC(C)c1ccc(S(=O)(=O)Cc2ccc(CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-acetamide (1.37 g, 4.13 mmol) in tetrahydrofuran (30 ml) was refluxed and then a solution of borane-dimethylsulfid complex (2M in tetrahydrofuran, 10.33 mmol) was added. The mixture was refluxed for 2 h. The mixture was allowed to cool down to room temperature and adjusted to pH=1 with a solution of HCl in ethanol (2M). After stirring the mixture for 15 min the solvents were evaporated under reduce pressure. Diethyl ether was added to residue. A slurry of the resulting white powder in diethyl ether was stirred for 15 min. The remaining solid was collected, washed with diethyl ether, and dried in a vacuum oven to give white crystals of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (1.36 g, 92.6%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:39][CH3:40])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:38])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:41])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:42])=[O:4])=[CH:12][CH:11]=2)=[C:14]([CH3:41])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[C:24]([CH3:38])[CH:23]=1)[CH2:39][CH3:40])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 100 °C
Yield: 58.7 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.50 mL, 1.0 mmol) was added to a solution of the mixture containing [4′-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (14.0 mg) in methanol (1.0 mL), and the mixture was stirred with microwave heating at 100° C. for five minutes. An ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate and washing with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 90:10) to give the target compound as a colorless oil (8.0 mg, 19% in two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH:13]=[CH:12][S:11][NH:10][C@@H:9]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CC=CCCC=C1.C1C=CN=CC=1.F[P-](F)(F)(F)(F)F.[Ir]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][NH:10][C@@H:9]2[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc([C@H]2NSC=C[C@@H]2c2cccc(Cl)c2)cc1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1=CCCC=CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1ccc([C@H]2NSCC[C@@H]2c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 4.14 g (11.69 mmol) of (3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,2-thiazin (Example 117, Step B) in dichloromethane (63.0 mL) was purged with argon three times, and then Crabtree's catalyst (835.2 mg, 1.027 mmol) was added to the reaction mixture. The reaction was purged again with argon, and then a hydrogen atmosphere was placed over the reaction. The solution was stirred at ambient temperature for 15 hours, at which point the reaction was concentrated down to an oil. Purification by flash chromatography on silica gel (0 to 4% MeOH in DCM gradient) provided the title compound as a tan solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]2=[CH:23][CH:22]=[CH:21][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2Cl)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccccc2Cl)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2-chloro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 376 (M+H)+.