Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([NH:47][C:48](=[N:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])SC)([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(N(CC)CC)C.CCN(C(C)C)C(C)C>CN(C)C=O>[C:52]([NH:51][C:48](=[N:47][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:21][OH:22])=[O:18])[NH:11][C:9](=[O:10])[CH:8]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53]
Reactant: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCN)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1ccc([C@H](CO)NC(=O)[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 55 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-[2-hydroxy-1-(4-methoxyphenyl) ethyl]ornithine amide hydrochloride (0.57 g; 1.11 mmol; from step (d) above), N,N'-bis(Cbz)-S-methylisothiourea (0.44 g; 1.22 mmol), triethylamine (0.17 g; 1.67 mmol; instead of DiPEA) and dimethyl formamide (10 mL), 60 hours reaction time. Concentration under vacuum gave the crude product which was chromatographed on silica eluting with CH2Cl2 :EtOAc (3:1), then CH2Cl2 :EtOAc (1:1), to give pure sub-title compound as a solid (0.48 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26](Cl)=[O:27])[CH:21]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:22]1[CH:21]=[C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)[N:24]([CH3:25])[N:23]=1)=[O:27]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1nc(C(=O)Cl)cc1-c1ccco1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1-c1ccco1
Yield: 75.9 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.432 mmol), 5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carbonyl chloride (0.096 g; 0.454 mmol), and triethylamine (0.156 mL; 1.08 mmol) in dichloromethane (2.87 mL). Flash chromatography on silica gel eluting with 5% of ethyl acetate in dichloromethane gave 0.121 g (98%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carboxamide as a solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>O1CCCC1>[Br:1][C:2]1[N:3]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:4](=[O:13])[C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Oc1nc(Br)cnc1NC1CCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(Br)cnc(NC2CCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a suspension of CaH2 (1.7246 g, 40.96 mmol) in 80.0 mL tetrahydrofuran (0.50 M) was added 5-bromo-2-(N-cyclobutylamino)-3-hydroxypyrazine (EX-115C) (5.0477 g, 20.68 mmol) in 50.0 mL tetrahydrofuran (0.41 M) dropwise via an addition funnel. The resulting suspension was heated to reflux for 30 minutes. To the mixture was then added a solution of tert-butyl bromoacetate (3.40 mL, 23.03 mmol) in tetrahydrofuran (2.3 M). Refluxing of the mixture was continued for 18 hours. The reaction mixture was allowed to cool to room temperature and cautiously poured in to a stirred ice water mixture (600.0 mL). The aqueous layer was extracted with ethyl acetate (4×250 mL). The combined organic solutions were washed with saturated NaHCO3 (1×250 mL) and brine (2×250 mL). The organic solution was dried (MgSO4), filtered, and concentrated. Purification of the crude product by MPLC (20% ethyl acetate/hexanes) afforded pure 6-Bromo-1-t-butoxycarbonylmethyl-3-(N-cyclobutylamino)pyrazinone (EX-115D) in 72% yield as an off white solid: 1H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.18 (br d, J=7.5 Hz, 1H), 4.79 (s, 2H), 4.39-4.29 (m, 1H), 2.41-2.34 (m, 2H), 1.96-1.86 (m, 2H), 1.79-1.68 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.8, 152.5, 149.0, 124.6, 105.1, 83.3, 49.7, 46.3, 31.3, 28.2, 15.6; HRMS (EI) calcd for C14H21N3O3 358.0766, found 358.0746.
Reaction SMILES: [F:1][C:2]1([F:47])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30](C=O)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:35]([F:46])[C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH2:4][CH2:3]1.[C:48]([OH:51])(=O)[CH3:49].[CH3:52][NH:53][CH2:54]CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1([F:47])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([CH2:52][N:53]([CH2:49][CH2:48][OH:51])[CH3:54])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:35]([F:46])[C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(C=O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CC(=O)O
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCO)Cc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 70 mg (0.11 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formyl pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol obtained in Example (36-1) in 1.0 ml of tetrahydrofuran, 6.1 μl (0.11 mmol) of acetic acid, 26 μl (0.32 mmol) of 2-(methylamino)ethanol and 68 mg (0.32 mmol) of sodium triacetoxyborohydride were added, and the reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution and the reaction solution was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [dichloromethane/methanol/28% ammonia aqueous solution=95/4.75/0.25-80/19/1 (V/V/V)] to provide 68 mg of the title compound as a white solid (yield: 89%).
Reaction SMILES: CC([O:5][C:6]([NH:8][CH2:9][C:10]#[N:11])=[O:7])(C)C.C([NH:15][C@H:16]([C:19]([OH:21])=[O:20])CS)(=O)C.N>CO>[NH2:15][C:10](=[NH:11])[CH2:9][NH:8][C:6](=[O:7])[O-:5].[CH3:16][C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC#N
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: N
Solvent: CO
Product: CC(=O)O
Product: N=C(N)CNC(=O)[O-]
Yield: 62.6 %

Procedure:
N-Boc-aminoacetonitrile (40.2 g, 257.4 mmol) and N-acetylcysteine (42.0 g, 257.4 mmol) were dissolved in methanol (300 mL) at 60° C. and ammonia was passed through for 18 h. The solvent was removed in vacuo. After ion exchange chromatography (Amberlite IRA-400 (AcOH)) and recrystallisation from acetone, 28.4 g (53%) of the sub-title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH:4]1[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5]1.[H][H]>[Pd].CO>[CH3:1][N:2]([CH3:16])[CH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: [H][H]
Reactant: CN(C)CC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1CCNC1
Yield: 96.8 %

Procedure:
A mixture of 1.25 g (5.72 mmol) of N,N-dimethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 100 mL of methyl alcohol, 0.2 g of 20% palladium on carbon and hydrogen were shaken at a pressure of 55.1 psi. After 16.8 hours the catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was bulb to bulb distilled yielding 0.71 g (97%) N,N-dimethyl-3-pyrrolidinemethanamine as a clear yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:6])[NH2:5].C[O-].[Na+].C(#N)C.[CH2:13]([C:20]1[O:21][C:22](=[O:27])[C:23](=[CH:25]O)[N:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.O>[CH3:2][O:3][C:4]1[NH:5][C:22](=[O:27])[C:23]([NH:24][C:20](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][N:6]=1
Reactant: O=C1OC(Cc2ccccc2)=NC1=CO
Reactant: COC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: COc1ncc(NC(=O)Cc2ccccc2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
O-Methylisourea hydrochloride (0.11 g, 1.0 mmol) was dissolved in methanol (2 ml), and 28% sodium methoxide (0.19 g, 1.0 mmol) was added. Acetonitrile was added, and the mixture was concentrated. 2-Benzyl-4-hydroxymethylene-5-oxazolone (0.203 g, 1.00 mmol) was added, and the mixture was stirred overnight at 80° C. Water (3 ml) was added, and the mixture was stirred at room temperature for 1 hour. Then, the precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-phenylacetylamino-1,6-dihydropyrimidine (0.16 g, 0.62 mmol). The values of the shift in 1H-NMR were the same as those in Example 1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH:10]([OH:13])([CH3:12])[CH3:11]>>[CH3:11][C:10]([OH:13])([CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1])[CH3:12]
Reactant: CC(C)O
Reactant: C=C(C)c1ccccc1
Product: CC(CC(C)(C)O)c1ccccc1

Procedure:
By reaction of α-methylstyrene with isopropanol under the conditions described in example 1, after multistage distillation, a mixture which 2-methyl-4-phenyl-2-pentanol (90.3 GC area %) was obtained. In a 300 mL autoclave, 27.7 g of this mixture were dissolved in 132.3 g of tetrahydrofuran, and 1.6 g of a catalyst according to preparation example 1 were initially charged in a catalyst basket. The autoclave was purged three times with nitrogen. This was followed by hydrogenation at 160° C. and hydrogen pressure 160 bar for 10 hours. The output was analyzed by means of gas chromatography (30 m column material DB1 ID: 0.25 mm, FD: 0.25 μm, 50° C.-5 min isothermal, −6° C./min 290° C.-219 min isothermal). The composition of the output after 10 h is reported in the table below.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([NH2:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[F:9][C:10]1[C:15]([F:16])=[C:14]([C:17](O)=[O:18])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[CH3:22]>>[CH3:1][CH:2]([CH:4]([NH:8][C:17](=[O:18])[C:14]1[C:13]([F:20])=[C:12]([F:21])[C:11]([CH3:22])=[C:10]([F:9])[C:15]=1[F:16])[CH:5]([CH3:7])[CH3:6])[CH3:3]
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: CC(C)C(N)C(C)C
Product: Cc1c(F)c(F)c(C(=O)NC(C(C)C)C(C)C)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using 2,4-dimethylpentan-3-amine and 2,3,5,6-tetrafluoro-p-toluic acid (90%). 1H NMR (CDCl3) δ 0.91 (d, J=6.7 Hz, 6H), 1.00 (d, J=6.8 Hz, 6H), 1.85 (m, 2H), 2.29 (m, 3H), 3.82 (m, 1H), 5.52 (bd, 1H). MS (306.1, M+H) m. p. 184-187° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:7]1=[N:6]2.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].C>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]3[NH:21][N:20]=[N:19][N:17]=3)[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc(C)c2c(=O)n3cc(C#N)ccc3nc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1sc(C)c2c(=O)n3cc(-c4nnn[nH]4)ccc3nc12
Temperature: 120 °C
Yield: 60.4 %

Procedure:
A mixture of 4.4 g (0.0172 mol) of 1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile (Example 51), 6.5 g (0.1 mol) of sodium azide and 5.3 g (0.1 mol) of ammonium chloride in 180 ml of dimethylformamide is stirred and heated in a wax bath at 120° C. for seventeen hours under nitrogen. The reaction mixture is cooled, filtered and the filtrate evaporated. The residue is treated with 250 ml of water and acidified with concentrated hydrochloric acid. This mixture is warmed on a steam bath, cooled and filtered to give 5.1 g of crude product. This material is dissolved in hot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Mansville). The filtrate is cooled to give 3.1 g of 1,3-dimethyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno-[3,4-d]pyrimidin-10-one; mp 292° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:3]=1[NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:15]1[NH:14][C:3]2[C:4]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[N:1]=1
Reactant: CCN(CC)c1ccc(F)c(N)c1NC(=S)Nc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(F)c2nc(Nc3ccc(Cl)cc3Cl)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A mixture of 1-[2-amino-6-(diethylamino)-3-fluorophenyl]-3-(2,4-dichlorophenyl)thiourea (300 mg, 0.748 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.788 mmol) and triethylamine (0.115 mL, 0.825 mmol) in tetrahydrofuran (3 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (191 mg, 0.521 mmol, 70%).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][CH2:27]O)[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.S(Cl)([Cl:34])=O.CO>ClCCl>[O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][CH2:27][Cl:34])[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1
Reactant: O=C1O[C@@H](Cn2cc(CCO)nn2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1O[C@@H](Cn2cc(CCCl)nn2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Yield: 91.3 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-hydroxyethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 51) (300 mg, 0.66 mmol) was reacted with thionylchloride (78.5 mg, 1.98 mmol) as described for Example 52. Chromatography on silica gel with 2.5% methanol in dichloromethane gave the title compound (285 mg).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[O:38][C:34]4=[CH:35][CH:36]=[CH:37][C:33]4=[CH:32][CH:31]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[O:38]1[C:34]2=[CH:35][CH:36]=[CH:37][C:33]2=[CH:32][CH:31]=[C:30]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:20]1[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:39])=[O:3])=[CH:14][CH:13]=2)[N:19]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3-c3ccc4cccc-4o3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2-c2ccc3cccc-3o2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.04 (2H, d), 7.92 (2H, d), 7.58 (2H, dd), 7.26 (2H, m), 6.91(2H, d), 6.79 (2H, d), 4.17 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([NH:4][CH2:5][C:6]1([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CC(=O)NCC1(N2CCCCC2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCC1(N2CCCCC2)CCCCC1
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
A solution of 1-[1-(acetamidomethyl)cyclohexyl] piperidine (5.5 g.) in dry tetrahydrofuran (50 ml) was added dropwise with stirring during 10 mins. to a suspension of lithium aluminium hydride (3.8 g.) in dry tetrahydrofuran (100 ml). The mixture was heated under reflux for 51/2 hrs. and stirred at room temperature for 16 hrs. Water (10 ml) was added dropwise to decompose excess lithium aluminium hydride (grey suspension had turned white). The suspension was filtered through hyflo, washed with ether and the combined filtrates dried (anhyd. Na2SO4). The dried filtrate was evaporated to dryness under reduced pressure and the residual oil (5 g.) was distilled under high vacuum to give 1-[1-(Ethylaminomethyl)cyclohexyl]piperidine (3.5 g.). b.p. C 138°-144° at 5.5 mm.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[OH:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:3]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(O)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 3-(1-hydroxyethyl)phenol (7 g), 2-chloromethylquinoline (9 g), potassium carbonate (7 g) and potassium iodide (0.3 g) in acetone (75 ml) was refluxed overnight. The reaction mixture was poured into water, and then thoroughly extracted with ethyl acetate (3×30 ml). The organic extract was washed with NaOH solution (1N), water, brine, and then dried over MgSO4. All volatiles were removed to obtain a dark brown liquid, which was chromatographed on silica gel (12% ethyl acetate in hexanes) to leave the desired product as a light yellow liquid.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[S:15]1[CH:19]=[CH:18][N:17]2[CH:20]=[N:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.P([O-])([O-])([O-])=O>C1COCC1.ClCCl>[CH2:1]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[C:19]1[S:15][C:16]2=[C:22]([C:23]([O:25][CH3:26])=[O:24])[N:21]=[CH:20][N:17]2[CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COC(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)OC)c2s1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution (5 ml) of 0.716 g of tri-n-butylstannyl chloride in THF was added to a solution (20 ml) of 0.364 g of methyl imidazo[5,1-b]thiazole-7-carboxylate in THF at −70° C. A 1.0 N lithiumbis(trimethylsilyl)amide/n-hexane solution (4.4 ml) was added dropwise thereto at −70° C. The mixture was stirred at −50° C. for 30 min. The reaction solution was added to an ice cold mixed solution composed of 50 ml of 0.2 N phosphate buffer (pH 7) and 50 ml of dichloromethane with stirring. The organic layer was separated, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was subjected to separation and purification by flash column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 0.395 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[CH:10]([N-]C(C)C)(C)C.[Li+].[C:18](=[O:20])=[O:19]>C1COCC1>[CH3:10][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([C:18]([OH:20])=[O:19])=[C:4]([F:9])[C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1F
Reactant: CC(C)[N-]C(C)C
Reactant: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)c(C(=O)O)c(F)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-methylbenzene (21.9 g, 116 mmol) in THF (100 mL) was added lithium diisopropylamide (LDA) (2 M solution in THF, 69 mL, 139 mmol) at −78° C. After being stirred at −78° C. for 1 h, the reaction was treated with excess solid carbon dioxide, and stirred while the reaction temperature slowly rose to room temperature. The mixture was concentrated and then partitioned between 4N NaOH and ethyl acetate. The aqueous phase was adjusted to pH 2 with 2N HCl and then extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried over with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with EA to give methyl 6-bromo-2-fluoro-3-methylbenzoic acid (23.3 g, 86.2%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:21]([O:23]C)=[O:22].[I-].[Li+].N1C=CC=CC=1>O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A mixture of methyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (4.32 g), anhydrous lithium iodide (10.8 g) and dry pyridine (43 ml) was stirred at 120° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (900 ml). Insoluble materials were removed by filtration. The aqueous layer was adjusted to pH 5 with conc. hydrochloric acid to give crystals, which were filtered off, suspended in a mixture of chloroform and methanol, stirred and filtered to give crystals, which were dried to give crystalline 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylic acid (2.8 g).