Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:14].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:3]1[CH:4]=[C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)[CH:6]=[CH:7][C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1(c2ccc(Br)c(F)c2)CC1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: O=C(O)C1(c2ccc(-c3ccccc3)c(F)c2)CC1
Temperature: 130 °C
Yield: 214 %

Procedure:
800 mg (3.1 mmoles) of 4-bromo-3-fluorophenylcyclopropanecarboxylic acid and 650 mg (3.4 mmoles) of phenylboronic acid are suspended in 8 ml of a 2M K2CO3 aqueous solution. The mixture is added with tetrabutylammonium bromide (960 mg, 3 mmoles) and palladium(II) acetate (40 mg, 0.18 mmoles) and heated at 130° C. in a closed reactor for 30 minutes. After cooling at room temperature, the mixture is added with 2M HCl (25 ml) and extracted with ethyl acetate. The organic phase is washed with 1N HCl, then with brine, finally dried and concentrated under vacuum to give an oil (1.7 g), which is crystallized from isopropyl ether-hexane to afford the product as a white solid (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])(O)[C:9](Cl)([Cl:11])[Cl:10].ClC1C=CC=CC=1C(C1C=CC=CC=1Cl)C(Cl)(Cl)Cl.C1C(C(C(Cl)(Cl)Cl)C2C=CC(Cl)=CC=2)=CC=C(Cl)C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[C:9]([Cl:10])[Cl:11]
Reactant: OC(c1ccccc1Cl)(c1ccccc1Cl)C(Cl)(Cl)Cl
Agent: Clc1ccc(C(c2ccc(Cl)cc2)C(Cl)(Cl)Cl)cc1
Agent: Clc1ccccc1C(c1ccccc1Cl)C(Cl)(Cl)Cl
Product: ClC(Cl)=C(c1ccccc1Cl)c1ccccc1Cl

Procedure:
The present commercial process for manufacturing 1,1-bis(chlorophenyl)-2,2,2-trichloroethanol (dicofol) uses 1,1-bis(chlorophenyl)-2,2,2-trichloroethane (DDT) as the starting material. DDT is dehydrohalogenated with alkali to afford 1,1-bis(chlorophenyl)dichloroethylene, which is chlorinated to afford 1,1-bis(chlorophenyl)-1,2,2,2-tetrachloroethane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[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]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:31])[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]([NH:21][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([CH:28]2[CH2:29][CH2:30]2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)C2CC2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 5, using the following starting materials: (3-{4-amino-2-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester and 4-chlorobenzoyl chloride.
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[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[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(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][CH:71]([CH3:75])[C@@H:72]([NH2:74])[CH3:73]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][C@@H:72]([CH3:73])[CH:71]([CH3:75])[CH3:70])=[O:31])[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)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)[C@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@@H](C)C(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

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]-4-methylbenzoic acid (31 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and (2S)-3-methyl-2-butanamine (10.5 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 40%). LC-MS m/z 591 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15]1.O[N:29]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:29])=[O:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Temperature: 100 °C
Yield: 64 %

Procedure:
5-bromo-3-(1,1-dioxido-2-phenyltetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylic acid (0.9 g, 2.007 mmol) was put in a flask and dissolved in N,N-Dimethylformamide (DMF) (2 mL). HOBt (1-hydroxybenzotriazole) (0.271 g, 2.007 mmol) and EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (1.078 g, 5.62 mmol) were added. The mixture was stirred and 0.5N NH3 in dioxane was added (12.04 mL, 6.02 mmol). The reaction mixture was heated under microwave at 100° C. for 20 minutes. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×25 mL). Organic layers were combined and washed with a saturated aqueous solution of sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. The mixture was dissolved in the minimum amount of DCM and precipitated in hexane, giving 0.575 g of the title compound as a pale brown powder.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH2:9])[CH2:4][O:3]1.[Cl:11][C:12]1[C:13]([F:31])=[C:14]([F:30])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[Cl:29])=[C:16]([CH:20]=1)[C:17](O)=[O:18].OC(CO)CONC(=O)C1C=CC(F)=C(F)C=1NC1C=CC(I)=CC=1F>C(O)C>[Cl:11][C:12]1[C:13]([F:31])=[C:14]([F:30])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[Cl:29])=[C:16]([CH:20]=1)[C:17]([NH:9][O:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])=[O:18]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Agent: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CCO
Product: O=C(NOC[C@H](O)CO)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl

Procedure:
Prepared from (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine and 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid by the procedure described for N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide: m.p. 155-156° C.; [α]=−5.1° (c=3.5 mg/mL, ethanol); 1NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.83 (s, 1H), 7.76 (s, 1H), 7.66 (d, 1H, J=6.8 Hz), 7.47 (d, 1H, J=8.5 Hz), 6.68 (t, 1H, J=6.6 Hz), 4.83 (bs, 1H), 4.60 (bs, 1H), 3.89-3.92 (m, 1H), 3.68-3.76 (m, 2H), 3.30 (2H, partially hidden by HDO); MS (APCI+)=533.0/535.0; Anal. calcd/found for C16H13Cl2F2IN2O4: C, 36.05/36.04; H, 2.46/2.25; N, 5.25/5.10; F, 7.13/7.18; Cl, 13.30, 13.50; I, 23.80, 24.02.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][O:15][CH2:16][CH2:17][CH:18]=1)(=O)=O.[F:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1>COCCOC.CCOC(C)=O.O.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>[O:15]1[CH2:16][CH2:17][CH:18]=[C:13]([C:27]2[C:22]([F:21])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:14]1
Reactant: OB(O)c1cccnc1F
Reactant: O=S(=O)(OC1=CCCOC1)C(F)(F)F
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1ncccc1C1=CCCOC1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
Sodium carbonate (29.0 mL, 58.0 mmol, 2.0 M in water) was added via syringe to a stirred mixture of 5,6-dihydro-2H-pyran-3-yl trifluoromethanesulfonate (4.49 g, 19.3 mmol), 2-fluoropyridine-3-boronic acid (2.72 g, 19.3 mmol), and tetrakis(triphenylphosphine)palladium (1.12 g, 0.97 mmol) in DME (82 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 17 h. The reaction mixture was then cooled to room temperature before being diluted with EtOAc and water. The organic layer was separated, washed with sat. aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 3-(5,6-dihydro-2H-pyran-3-yl)-2-fluoropyridine. MS (ESI, pos. ion) m/z: 180.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>Cl>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:10]1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(C)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (25 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (13.2 g.) and acetic anhydride (75 g.) was heated (to 95° C.) during one hour, then refluxed with dilute hydrochloric acid (32 g. concentrated hydrochloric acid plus 160 ml. water) during one and one-half hours. The resulting mixture was poured onto ice and the pH was adjusted to 6 with sodium hydroxide. Recrystallization of the resulting product afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X=(CH3)2N, Y2 =CH3, Y4 =(CH3CH2)2N, Z4 =Z5 =Z6 =Z7 =H) in a first crop from toluene (m.p. 204°-206° C.) and in a second crop from a mixture of toluene and hexane (m.p. 191°-195° C.).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7]2[CH:8]=[N:9][N:10]([CH3:13])[C:11]=2[CH:12]=1.Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[CH:8]=[N:9][N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
Lithium hydroxide (156 mg, 6.51 mmol) was added to a stirred suspension of methyl 6-bromo-1-methyl-1H-indazole-4-carboxylate (730 mg, 2.71 mmol) in tetrahydrofuran (THF) (25 ml) and water (5 ml) and the reaction mixture was stirred at room temperature for 1 h. During this time the cream suspension turned to a pale brown solution. The reaction mixture was poured onto 2N HCl (100 ml) with stirring. The precipitate formed was filtered off under vacuum and dried at 50° C. in a vacuum oven for 18 h to give the title compound as a white solid (480 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])[C:9]#[CH:10].C(OC(C)C)(C)C>C(O)=O>[CH2:8]([O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH:22][CH:1]=[O:3])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])[C:9]#[CH:10]
Reactant: C#CCON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Formic acid (107 g.) was added to acetic anhydride (239 g.) under ice-cooling, and the mixture was stirred for 1 hour at 50° C. and then cooled to 20° C. To the mixture was added 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (135 g.), and the mixture was stirred for 3 hours at ambient temperature. To the mixture was added diisopropyl ether (400 ml.) and then the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (118.4 g.).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[N:5]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([N:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(N2CCC(O)CC2)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCSc1nc(N2CCC(=O)CC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A solution of 201 mg (0.5 mmol) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(4-hydroxy-piperidin-1-yl)-4-methyl-pyridine-3-carboxylic acid amide (example 15) in DCM (7 ml) was treated with 1.84 g (0.65 mmol, 15% w/w in DCM) Dess-Martin periodinane and stirred at RT for 3 h. The RM was then quenched by addition of a 10% (w/w) aq. Na2S2O3 sol. and diluted with DCM (30 ml). The organic layer was separated, washed with a 2M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 88 mg (0.22 mmol, 44%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(4-oxo-piperidin-1-yl)-pyridine-3-carboxylic acid amide (example 16). [M+H]+402.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[CH2:28]([O:27][C:25](=[O:26])[CH:24]([O:23][CH2:21][CH3:22])[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[O:17][CH:18]([CH3:20])[CH3:19])[OH:14])[CH3:29]
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOCC(=O)OCC
Product: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1OC(C)C

Procedure:
In analogy to the procedure described in example 47 a], 4-benzyloxy-2-isopropoxy-benzaldehyde [Chemical & Pharmaceutical Bulletin (1998), 46(2), 222-230] was reacted with the enolate of ethyl ethoxyacetate, to yield [rac]-3-(4-benzyloxy-2-isopropoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester as a mixture of diastereomers in form of a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:1][N:2]1[CH:7]=[C:6]([S:8]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:10])=[O:9])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)n(C)c1=O
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)NC(C)(C)C)c(=O)n(C)c1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a stirred suspension of 1,3-dimethyl-2,4-dioxo-5-pyrimidinesulfonyl chloride (300 g, 1.26M) in methylene chloride (2500 mL) at room temperature was added dropwise tert-butylamine (300 mL, 2.85M). The exotherm was allowed to proceed to 35° C. with mild cooling. After addition the reaction was refluxed for 30 minutes, cooled to room temperature and the tert-butylamine.HCl filtered off. The methylene chloride was then washed with diluted hydrochloric acid (700 mL), dried over MgSO4, and stripped under vacuo. Recrystallization of the white solid from ethanol afforded the desired compound (652 g, 94%) in three crops, m.p. 143°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27]>O>[Cl:1][C:2]1[C:3]([O:12][CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: CCCCCOC(=O)CCl
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenol (100 g), anhydrous potassium carbonate (86.6 g) and dimethylformamide (500 g) was heated at 50° C., and amyl 2-chloroacetate (90.2 g) was dropwise added thereto in 30 minutes, followed by allowing to stand at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and water (1500 g) was added thereto, followed by extraction with ethyl acetate (1500 g). The organic layer was separated, washed with water and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)nitrobenzene (Compound (III)) (129 g) as a pale yellow oil. Yield, 77%. b.p., 160 °-165° C./0.7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][CH:61]([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][CH:61]([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)F)C4CC4)c23)c(C)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (112.9 mg, 0.283 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (142.8 mg, 0.566 mmol) and tributylphosphine (141.0 μL, 0.566 mmol). After 10 min, to the mixture was added 2,2-difluoroethanol (179.2 μL, 2.830 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (62.0 mg, 0.134 mmol, 47%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].C(OC)(OC)OC.[C:21]([O:25][C:26](=[O:37])[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1)([CH3:24])([CH3:23])[CH3:22].[BH4-].[Na+]>CO>[C:21]([O:25][C:26](=[O:37])[NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[CH:33][CH:34]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCOCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCOCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
The compound (81.0 mg) obtained in Example 90-3 was dissolved in anhydrous methanol (2.0 ml) and added with trimethyl orthoformate (94.1 μl) and the compound (101 mg) obtained in Example 23-3 and the whole was stirred overnight at room temperature under a nitrogen atmosphere. Subsequently, sodium borohydride (32.6 mg) was added thereto in an ice bath and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with distilled water and the whole was stirred for a while. The resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (158 mg) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.C1C(=O)N([I:16])C(=O)C1>C(O)(=O)C>[I:16][C:7]1[C:2](=[O:1])[NH:3][CH:4]=[N:5][C:6]=1[CH3:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(O)ncn1
Solvent: CC(=O)O
Product: Cc1nc[nH]c(=O)c1I
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred solution of 70 g (0.64 mol) 4-hydroxy-6-methylpyrimidine in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min. The reaction is stirred for 30 h at RT until all starting material is consumed. The reaction mixture is diluted with water and the solid product is filtered off and washed with sodium thiosulfate solution to remove excess iodine. After drying, the desired product is obtained as a pale brown solid (90 g; 60%) which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH2:24]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[OH:28]>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH:24]=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)n1c(CBr)cc2c(Cl)nc(-c3ccccc3)nc21
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(C=O)cc2c(Cl)nc(-c3ccccc3)nc21
Temperature: 48 °C
Reaction time: 1 h

Procedure:
A suspension of the bromide 7 (2.00 g, 4.73 mmol), Na2HPO4 (806 mg, 5.68 mmol) and NaH2PO4 (227 mg, 1.89 mmol) in DMSO (50 mL) is heated under nitrogen to 48° C. After 1 h, all solids are dissolved, and the reaction is continued for 2 h. The solution is then poured in H2O (600 mL), and the mixture is extracted with EtOAc (2×150 mL). The combined EtOAc layers are washed with H2O (3×400 mL) and brine and dried over MgSO4. Filtration and concentration yields a yellow solid, which is triturated with EtOH giving 1.06 g (2.97 mmol, 63%) of the title compound as a yellow solid. MS (ES): m/z 304.7/306.7 (33/10) [MH+-Boc-H2O+2 MeOH], 272.7/274.7 (100/32) [MH+-Boc-H2O+MeOH]. 1H NMR (200 MHz, CDCl3): δ=1.79 (s, 9H), 7.44 (s, 1H), 7.48-7.55 (m, 3H), 8.51-8.60 (m, 2H), 10.39 (s, 1H). tR (method A)=10.4 min.