Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([O-:7])=[O:6].[Na+].C(O)C.S(O[CH:43]([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])(C1C=CC(C)=CC=1)(=O)=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([O:7][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:49])=[O:6]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1F
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)OCC)cc1F

Procedure:
To a warm mixture of 7 g sodium 3-fluoro-4-(hexadecylamino)benzoate in 100 ml. ethanol is added 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 3-fluoro-4-(hexadecylamino)benzoate as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:4](=[O:7])[NH:5][N:6]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:5]1[C:4](=[O:7])[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:2]([Br:1])=[N:6]1
Reactant: COC(=O)CCl
Reactant: O=c1[nH]nc(Br)n1Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Cn1nc(Br)n(Cc2ccccc2F)c1=O

Procedure:
300 mg (1.1 mmol) of the compound from Example 135A are stirred under reflux for 2 hrs together with 150 mg (1.38 mmol) of methyl chloroacetate and 168 mg (1.21 mmol) of potassium carbonate in 10 ml acetonitrile. After cooling, the mixture is diluted with ethyl acetate and treated with 1 N hydrochloric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and freed of the volatile components on the rotary evaporator. The residue is dried under high vacuum. The product thus obtained (360 mg, purity ca. 73% by LC/MS) is used in the next synthetic step without further purification.
Reaction SMILES: C(O[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC([N:27]1[C:31]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=2[N:29]=[CH:28]1)=O)(C)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([C:28]3[NH:27][C:31]4[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=4[N:29]=3)=[O:19])=[CH:10][CH:9]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: CCOC(=O)c1ccc(Oc2nccnc2Cl)cc1
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccc(F)cc2[nH]1
Reaction time: 3.5 h

Procedure:
A solution of 4-(3-Chloro-pyrazin-2-yloxy)-benzoic acid ethyl ester (20 g, 84.7 mmol) and 6-fluoro benzoimidazole-1-carboxylic acid tert-butyl ester (21.2 g, 76.3 mmol) in freshly dried THF (150 mL) was cooled to −78° C. LiHMDS (106 mL, 106 mmol) was added slowly to it over 1.2 h. The reaction mixture was stirred at the same temperature for 3.5 h. The reaction was brought to −20° C. and slowly quenched with addition of 2N HCl until pH 3-4. The resulting mixture was stirred at RT for 1 h, extracted with ethyl acetate (3×200 mL), and washed with water (2×100 mL). The organic layer was dried (Na2SO4) and concentrated. To the crude product was added methanol (70 mL). After stirring for 1 h, the solid was collected by filtration to give the title compound. MS (ESI, pos. ion) m/z: 369.2 (M+1). IC50 (uM) +.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[Br:12]>[OH-].[Na+]>[Br:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[SH:4]
Reactant: CN(C)C(=O)Sc1cc(F)ccc1Br
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(Br)c(S)c1
Yield: 99 %

Procedure:
51.30 g of S-(2-bromo-5-fluorophenyl) dimethylthiocarbamate were dissolved in 700 ml of MOH, 494 ml of a 1 N aqueous sodium hydroxide solution were added and the reaction mixture was heated for 2 h under reflux. After cooling, the MOH was removed in vacuo, 200 ml of water were added and the mixture was extracted three times with 150 ml each of DCM. Subsequently, the mixture was acidified to pH=1 with concentrated hydrochloric acid and extracted four times with 200 ml each of EA. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. 37.80 g of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17](C(OCC)=O)=[C:16]([CH3:23])[N:15]=[C:14]3[S:24][C:25]([C:28]4[CH:29]=[N:30][NH:31][CH:32]=4)=[C:26]([CH3:27])[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C(O)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:23])[N:15]=[C:14]3[S:24][C:25]([C:28]4[CH:32]=[N:31][NH:30][CH:29]=4)=[C:26]([CH3:27])[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(C)c2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: O=CO
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cn[nH]c3)sc2n1
Temperature: 150 °C
Yield: 9.4 %

Procedure:
A mixture of ethyl 4-{[(3-chlorophenyl)sulfonyl]amino}-3,6-dimethyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 64) (150 mg, 0.306 mmol) in DMSO (5 mL) and aqueous NaOH (2M) (0.611 mL, 3.06 mmol) was heated at 150° C. for ca. 1.5 h. After cooling to RT, the mixture was diluted with water (20 mL), acidified with formic acid (ca. pH 4-5) and extracted with 10% MeOH in DCM (30 mL×5). The combined organics were dried and concentrated. The residue was passed through a C18 solid phase extractor cartridge, eluting with water (30 mL×4) and then with MeOH (30 mL×4) and the combined organics concentrated. The residue was taken-up in diphenyl ether (2 mL, 12.57 mmol) and DMSO (0.5 mL) and the mixture was heated at 200° C. for ca. 45 min. After cooling to RT, the mixture was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in cyclohexane and then with 0-20% MeOH in DCM and then further purified by MDAP (acidic conditions), to give the title compound (12 mg). LCMS (A) m/z: 419 [M+1]+, Rt 1.04 min (acidic).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].F[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[OH:6][CH2:5][CH2:4][CH2:3][O:7][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: Oc1ncnc2cc(F)ccc12
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCOc1ccc2c(O)ncnc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Sodium hydride (14.6 g, 365 mmol) was added at 0° C. to a solution of 1,3-propanediol (27.8 g, 365 mmol) in dimethylformamide (70 ml). 7-Fluoroquinazolin-4-ol (10 g, 60.9 mmol) was added portion wise and the reaction mixture heated at 60° C., then at 110° C. for 3 hours. The reaction was cooled to 0° C., quenched with water (280 ml) and adjusted to pH 5.9. The resulting suspension was filtered, washed with water then diethyl ether and dried over phosphorus pentoxide to yield 7-(3-hydroxypropoxy)quinazolin-4-ol as a white powder (12.41 g, 92% yield):
Reaction SMILES: [Cl-].[CH:2](=[N+:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[OH:25]>>[N:9]1([CH:2]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[OH:25])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: Oc1ccc2ccccc2c1
Reactant: C(c1ccccc1)=[N+]1CCOCC1
Agent: [Cl-]
Product: Oc1ccc2ccccc2c1C(c1ccccc1)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-benzylidene-morpholin-4-ium chloride and 2-naphthol.
Reaction SMILES: Cl.Cl[C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]=1.[CH3:24][O-:25].[Na+]>CO>[CH3:24][O:25][C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]=1
Reactant: C[O-]
Reactant: ClC(C1=NCCCCCN1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(C1=NCCCCCN1)(c1ccccc1)c1ccccc1

Procedure:
2-(Chlorodiphenylmethyl)-1,4,5,6,7,8-hexahydro-1,3-diazocine hydrochloride (0.001 mole) is stirred at room temperature for 2 days in a solution of dry methanol (5 ml) containing sodium methoxide (0.002 mole). After removal of solvent the residue is dissolved in chloroform and washed with water. After drying over magnesium sulphate the solvent is removed to give the title compound.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:67])[C:55]4[C:59]([CH:60]=3)=[N:58][N:57](C3CCCCO3)[CH:56]=4)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:67][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccccc1
Reaction time: 0.08 h

Procedure:
Benzoic acid (10 mg, 0.08 mmol) in DMF (0.2 mL) was treated with HATU (27 mg, 0.07 mmol) in DMF (0.2 mL) and DIPEA (30 μL, 0.24 mmol). The reaction mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.2 mL). Reaction mixture was shaken for five minutes and left to stand at 22° C. for 18 hrs. Solvent was removed in vacuo and the product re-dissolved in methanol (1 mL) prior to application on to an SCX cartridge (1 g). Product was eluted after 1 hr with 2M ammonia in methanol (2×3 mL), fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method D) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:23][C@@H:24]2[C@@H:31]3[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]3)[C@H:26]([N:34]3[C:38]4[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=5[O:53][CH3:54])[C:37]=4[CH:36]=[CH:35]3)[CH2:25]2)[CH2:21][CH3:22])[CH2:17]1>C(O)(=O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH2:15][CH:16]3[CH2:17][CH:18]([N:20]([CH2:23][C@@H:24]4[C@H:31]5[O:30][C:29]([CH3:33])([CH3:32])[O:28][C@H:27]5[C@H:26]([N:34]5[C:38]6[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH2:44][C:45]7[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=7[O:53][CH3:54])[C:37]=6[CH:36]=[CH:35]5)[CH2:25]4)[CH2:21][CH3:22])[CH2:19]3)=[N:1][C:2]=2[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Solvent: CC(=O)O
Product: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Yield: 96.2 %

Procedure:
A solution of N-(2-amino-4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanamide (0.88 g, 1.2 mmol) in Acetic acid (3 mL) was stirred overnight at 60° C., the volatiles removed in vacuo and remaining residue purified by flash chromatography (DCM/7N NH3 in MeOH 93:7) to give the desired compound (0.85 g) as a foam.
Reaction SMILES: [C:1]([C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:40])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][C:30]3[N:35]=[CH:34][C:33]4[O:36][CH2:37][CH2:38][O:39][C:32]=4[CH:31]=3)C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1)#[N:2].[ClH:41].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)C>[ClH:41].[O:39]1[C:32]2[CH:31]=[C:30]([CH2:29][NH:21][CH:18]3[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]4[C:11]5[N:12]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=5[CH:7]=[CH:8][C:9]4=[O:40])[CH2:20][CH2:19]3)[N:35]=[CH:34][C:33]=2[O:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ccc(C#N)nc32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of 1,1-dimethylethyl {1-[2-(7-cyano-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)carbamate (600 mg, 1.100 mmol) in DCM (10 ml) at 0° C. was added 1M HCl in diethyl ether (10 ml) and the reaction was stirred at 0° C. for 0.5 h and then allowed warm to rt and stirred at rt for 2 h before evaporation, treatment with sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (314 mg, 64%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C([Si](C)(C)[O:68][CH2:69][CH2:70][O:71][C:72]1[N:77]=[CH:76][C:75]([NH2:78])=[C:74]([O:79][CH3:80])[CH:73]=1)(C)(C)C>ClCCl>[OH:68][CH2:69][CH2:70][O:71][C:72]1[N:77]=[CH:76][C:75]([NH:78][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:74]([O:79][CH3:80])[CH:73]=1
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ncc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCO)ncc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 45.7 %

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol) in dichloromethane (9 mL) was added diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (Aldrich) (0.24 g, 1 mmol) respectively. The mixture was stirred at room temperature for 8 min, then 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-methoxy-pyridin-3-ylamine prepared in Example 191 (0.23 g, 0.78 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated. The residue was dissolved into tetrahydrofuran (3 mL), and an aqueous solution (1N) of HCl (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (0-15% MeOH in CH2Cl2) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [6-(2-hydroxy-ethoxy)-4-methoxy-pyridin-3-yl]-amide as a white solid (0.15 g, 46%).
Reaction SMILES: [C@@H:1]12[C:7](=[O:8])[NH:6][C@@H:5]1[CH2:4][CH2:3][NH:2]2.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:8]=[C:7]1[C@@H:1]2[C@@H:5]([CH2:4][CH2:3][N:2]2[C:16](=[O:17])[NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1N[C@@H]2CCN[C@H]12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1N[C@@H]2CCN(C(=O)Nc3ccccc3)[C@H]12

Procedure:
100 mg (0.89 mmol) of (1S,5R)-2,6-diazabicyclo[3.2.0]heptan-7-one were dissolved in 5 ml of chloroform and heated to boiling under reflux. Phenyl isocyanate (0.1 ml, 0.89 mmol) and 1 drop of triethylamine were added thereto and the mixture was left to react at the boiling temperature for 1 hour. After concentration the residue was chromatographed over silica gel (0.063-0.2 mm particle size) with ethyl acetate:ethanol=3:2.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:9]1[N:13]([CH2:14][CH3:15])[N:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7])=[O:4].[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][O:27][CH3:28])[C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([N:13]1[C:9]([N:5]([CH:6]([CH3:8])[CH3:7])[C:3](=[O:4])[CH2:2][O:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][O:27][CH3:28])[C:18]=2[CH:19]=[O:20])=[CH:10][CH:11]=[N:12]1)[CH3:15]
Reactant: COCOc1cccc(O)c1C=O
Reactant: CCn1nccc1N(C(=O)CCl)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nccc1N(C(=O)COc1cccc(OCOC)c1C=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
2-Chloro-N-(1-ethyl-1H-pyrazol-5-yl)-N-isopropylacetamide (0.39 g, 1.7 mmol) and 2-hydroxy-6-(methoxymethoxy)benzaldehyde (0.309 g, 1.7 mmol) were dissolved in DMF (8.5 ml) and purged with N2 gas. Potassium carbonate (0.47 g, 3.4 mmol) was added and the mixture was stirred in a heat block at 60° C. After 2 h, the reaction was cooled and partitioned into ethyl acetate (100 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with water (50 ml) and a saturated aqueous sodium chloride solution (50 ml), and dried over sodium sulfate. After evaporation the residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to give 0.38 g (59%) of N-(1-ethyl-1H-pyrazol-5-yl)-2-(2-formyl-3-(methoxymethoxy)phenoxy)-N-isopropylacetamide as a faintly-colored viscous oil. MS (ESI) m/z 376 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1>C(Cl)Cl>[N:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[NH:53][C:30](=[O:31])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:18]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
3-[6-(4-t-Butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid (121 mg) was dissolved in methylene chloride (0.9 ml). Oxalyl chloride (27 mg) and dimethylformamide (1 droplet) were added, and the mixture was stirred for 30 minutes at room temperature. 2-Aminopyridine (38 mg) was added, and the mixture was stirred overnight at room temperature. After the solvent was evaporated, ethyl acetate was added. The organic layer was successively washed with 0.5N-HCl, sat. aq. NaHCO3, and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1), to thereby obtain 51 mg (yield: 37%) of the title compound as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][S:9]C(=O)C.[OH-].[Na+]>CO>[SH:9][CH2:8][CH:7]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6]([NH:5][C@H:4]([C:3]([OH:25])=[O:2])[CH2:21][CH2:22][S:23][CH3:24])=[O:20]
Reactant: COC(=O)[C@H](CCSC)NC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)C(CS)Cc1ccccc1)C(=O)O

Procedure:
Dissolve the product of Step 1 in methanol (20 ml) and treat with 1N NaOH (20.4 ml) as described in Example 1, Step 2 to give the title compound, a white solid, m.p. 132°-5°, [α]D26 =-34.6° (MeOH).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=3)[N:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)ccc2c1
Product: FC(F)(F)Oc1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
The title compound is being prepared in a manner analogous to Example 3, Step D from the 2-chloro-6-trifluoromethoxy-quinoline of Step D and piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Na+].[Na+].FC1C(F)=C(OCCCCCCCC)C=CC=1C1N=CC(Br)=CN=1>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.COCCOC>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: N#Cc1ccc(-c2ncc(Br)cn2)cc1
Yield: 81.1 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine 2 (2.50 g, 8.77 mmol), 4-cyanophenylboronic acid 13 (1.42 g, 9.65 mmol), tetrakis(triphenylphosphine)palladium (304 mg, 0.26 mmol), DME (50 ml), aqueous 2M sodium carbonate (50 ml). The experimental procedure was as described for compound 4 to yield the cyanophenylpyrimidine 14 (1.85 g, 81%) (from MeOH), m.p. 222° C.; νmax /cm-1 (KBr) 2200 (CN), 1520, 1420s, 1120, 1015, 860 and 790; δ 7.76 (2H, d, 3'- and 5'-H), 8.54 (2H, d, 2'- and 6'-H) and 8.83 (2H, s, 4- and 6-H); m/z 261 (M+), 259 (M+), 234 (M+ -HCN), 232 (M+ -HCN), 153 and 128.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:14])[N-:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].C([Na])C.Cl>CO>[CH3:13][S:12][C:9]1[NH:8][C:7](=[O:14])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(SC)[n-]c1=O
Agent: CC[Na]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cnc(SC)[nH]c1=O

Procedure:
Ethyl sodium 5-(ethoxycarbonyl)-2-(methylthio)-4-oxo-4H-pyrimidin-3-ide (3.31 g, 14.00 mmol) was dissolved in 300 mL of methanol. 2 mL of HCl was added to the solution, which was condensed to yield the product.