Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:3])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 71 %

Procedure:
An excess solution of diazomethane in ether was slowly added to an ice-cooled and stirred solution of p-chlorobenzoic acid (6.2 g, 39.6 mmol) in 50 ml of ether and the mixture was concentrated. The residue was recrystallized from 5 ml of MeOH to give a white crystalline product of methyl p-chlorobenzoate (4.8 g, 28.2 mmol, yield 71%). m.p. 42.0°-43.0° C. (recrystallized from methanol)
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12](O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[N:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:12]=1[C:11]1[C:2](=[O:1])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Product: O=c1[nH]c2ccccc2cc1-c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1-1 (500 mg, 2.64 mmol, 1 equiv, prepared by the method of Marsais, F; Godard, A.; Queguiner, G. J. Heterocyclic Chem. 1989, 26,1589) and 1,2-phenylenediamine (344 mg, 3.18 mmol, 1.20 equiv) in polyphosphoric acid (15 mL) was heated under argon at 200° C. for 4.5 h. The hot reaction mixture was poured over ice (200 g), and the resulting mixture was allowed to stand overnight (20 h). The precipitate was filtered, washed with water (200 mL), and air dried to give the title compound as an olive-colored solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.58 (s, 1H), 9.15 (s, 1H), 7.94 (br d, 1H, J=7.5 Hz), 7.78 (dd, 2H, J=5.6, 2.9), 7.63 (br t, 1H, J=7.5 Hz), 7.42 (br d, 1H, J=8.2 Hz), 7.33 (dd, 2H, J=5.9, 2.9), 7.25 (br t, 1H, J=7.5 Hz); HRMS (electrospray FT/ICR) calculated for C16H12N3O [M+H]+ 262.0975, found 262.0981; anal. calcd for C16H11N3O+1.10 H3PO4+0.75 H2O: C, 50.23; H, 4.16; N, 10.98. Found C, 50.24; H, 4.21; N, 10.93.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([NH2:10])=[O:9].Cl[C:13]1[S:14][CH:15]=[CH:16]N=1.N>O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[N:10]1[CH:16]=[CH:15][S:14][C:13]1=[N:11]2
Reactant: Cc1cccc(N)c1C(N)=O
Reactant: Clc1nccs1
Agent: N
Solvent: O
Product: Cc1cccc2nc3sccn3c(=O)c12
Temperature: 140 °C
Yield: 68.8 %

Procedure:
While stirring, 22.5 g of 6-methylanthranilamide was added to 18 g of 2-chlorothiazole. The reaction mixture was heated over a 20-minute period to 140° C. and stirred for 4 hours. Water was added to the reaction mixture, and a pH of 10 was set by adding 25% strength ammonia solution. Working up in the conventional manner gave 22.3 g (69%) of compound 3; m.p. 148°-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.[C:41]1([CH3:65])[CH:46]=[CH:45][C:44]([S:47]([O:50][CH2:51][CH2:52][CH2:53]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:49])=[O:48])=[CH:43][CH:42]=1>>[CH3:39][O:38][CH2:37][CH2:36][CH2:35][N:31]1[C:30]2[CH:40]=[C:26]([CH2:25][O:24][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:53][CH2:52][CH2:51][O:50][S:47]([C:44]5[CH:43]=[CH:42][C:41]([CH3:65])=[CH:46][CH:45]=5)(=[O:48])=[O:49])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:10]3)[CH:27]=[CH:28][C:29]=2[O:34][CH2:33][CH2:32]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21

Procedure:
Analogously to Method I, 0.204 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.514 g of 1,3-propanediyl di-p-toluenesulphonate are reacted. The title compound is obtained as an orange oil. Rf=0.37 (2:1 EtOAc-heptane); Rt=5.72.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].[ClH:12].[C:13]1(C)[CH:18]=CC=C[CH:14]=1>C(O)(C)C>[ClH:12].[NH2:1][C@@H:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([O:6][CH:13]([CH3:18])[CH3:14])=[O:5]
Reactant: CC(C)CC(N)C(O)C(=O)O
Reactant: Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Temperature: 25 °C

Procedure:
3-Amino-2-hydroxy-5-methylhexanoic acid (Example A), 26.5 g (0.164 mol), is dissolved in isopropyl alcohol, treated with hydrochloric acid (anhydrous) for five minutes, treated with toluene (250 ml) and 3A molecular seives and warmed to reflux for 15 minutes. The solution is cooled to room temperature, filtered, and the solvents evaporated in vacuo to give the title compound as an extremely hygroscopic foam, 40 g. The foam is used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11]C(=O)OCC2C=CC=CC=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][N:9]=1
Reactant: [H][H]
Reactant: CCCCc1ccc(NC(=O)OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1ccc(N)nc1
Yield: 99.6 %

Procedure:
A mixture of benzyl (5-n-butyl-2-pyridyl)carbamate (6.5 g. 22.86 mmoles) and 10% palladium on carbon (2.7 g.) in ethanol (400 ml.) was shaken at room temperature for 2 hours in an atmosphere of hydrogen at an initial pressure of 3.52 kg./cm.2The mixture was filtered and the filtrate reduced to dryness to leave 2-amino-5-n-butylpyridine (3.42 g., 99.7%), m.p. 30°-33° (lit. m.p. 35°-36° in Helv. Chim. Acta, 39, 505 (1956).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])C(=O)[CH2:14][CH2:13]2.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH2:14][CH2:13]2
Reactant: O=CN1CCNCC1
Reactant: COc1cc2c(cc1F)CCC2=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: COc1cc2c(cc1F)CCC2N1CCNCC1
Yield: 87.9 %

Procedure:
1-Formyl-piperazine (2.1 g, 20 mmol), 5-fluoro-6-methoxy-indan-1-one (1.8 g, 10 mmol), titanium(IV) isopropoxide (5 ml, 15 mmol), and sodium borohydride (1.2 g, 30 mmol) were reacted by Method B to give the product (2.2 g, 88%, mp 163°-166° C.). Calcd for C14H19 FN2O.C4H4O4.0.1H2O: C, 56.23%; H, 6.56%; N, 7.28%. Found: C, 56.65%; H, 6.41%; N, 6.98%.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12]O.Br>ClCCl>[BrH:10].[Br:10][CH2:11][CH2:12][NH:9][C@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: OCCBr
Agent: Br
Solvent: ClCCl
Product: C[C@@H](NCCBr)c1ccccc1
Temperature: 51 °C
Reaction time: 50 h
Yield: 108.6 %

Procedure:
76.61 g (630 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g (760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml (2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10.C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate, and then dried to obtain 127.5 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.Cl.[N:17]1([CH2:22][CH2:23][N:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>O>[CH3:12][CH:11]1[C:3]2[C:2]([N:36]3[CH2:35][CH2:34][CH:33]([C:25]4[N:24]([CH2:23][CH2:22][N:17]5[CH2:18][CH2:19][CH2:20][CH2:21]5)[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[N:26]=4)[CH2:38][CH2:37]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1
Reactant: CC1CC(=O)Nc2ncnc(Cl)c21
Reactant: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCN4CCCC4)CC3)c21
Temperature: 200 °C

Procedure:
Add 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.22 g, 1.11 mmol), 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine trihydrochloride (0.57 g, 1.2 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (1.16 mL, 6.0 eq) in a microwave tube. Seal the tube and heat in a microwave reactor at 200° C. for 30 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 1-10% methanol/dichloromethane gradient, to give 5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a racemate (0.19 g, 36%). MS (ES) m/z=478 [M]+. Chiral separation (Chiralpak AD-H, 30% ethanol/70% CO2 w/0.2% isopropylamine) provides enantiomer 1 (>99% ee) and (R)-5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as enantiomer 2 (>99% ee). MS (ES) m/z=478 [M]+ for both compounds.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:19][NH:20][C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][CH2:42]Br)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O.O1CCCC1>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]([CH2:42][CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:38])[N:20]=[C:11]3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1n[nH]c2c1CCc1cnc(Nc3ccccc3)nc1-2
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c(nn1CCCNC(=O)OC(C)(C)C)-c1nc(Nc3ccccc3)ncc1CC2

Procedure:
500 mg of ethyl 8-anilino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.5 mmol) were dissolved in 10 mL of dry dimethylformamide and 1.63 mL of 1M lithium tert-butoxide in tetrahydrofuran were added to the cooled solution. After 30 minutes under stirring at 0° C. a solution of 432 mg of tert-butoxycarbonylaminopropyl bromide in 8 mL of dry tetrahydrofuran were added dropwise. After a night at room temperature the mixture was poured into a solution of NaH2PO4 and extracted with dichloromethane. The organic layer was then dried over Na2SO4 and the solvent evaporated, giving an oil that was treated according to the following step 7, without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([O:39]C)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([OH:39])=[O:38])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(OC)cc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N2CN(Cc3cccc(C(=O)O)c3)C(=O)C23CCN(CCCn2c(=O)[nH]c4ccccc42)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.32 g, 0.55 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.046 g, 1.1 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.15 g, 48%); 1H NMR (DMSO-d6): δ 1.64 (d, 2H, J=13.6 Hz), 1.77 (t, 2H, J=6.4 Hz), 1.95-2.02 (m, 2H), 2.31 (t, 2H, J=6 Hz), 2.57-2.67 (m, 4H), 3.68 (s, 3H), 3.79 (t, 2H, J=6.8 Hz), 4.34 (d, 4H, J=26.8 Hz), 6.84 (dd, 2H, J=4.8 and 2 Hz), 6.92-6.96 (m, 5H), 7.09-7.12 (m, 1H), 7.49-7.52 (m, 2H), 7.86-7.87 (m, 2H), 10.77 (s, 1H), 12.95 (br, 1H); MS for C32H35N5O5 m/z 570.04 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:13]C(C)(C)C)=[N:4][C:5]([O:8]C(C)(C)C)=[N:6][CH:7]=1.C([Li])CCC.[CH3:23][C:24]1[O:25][C:26]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:30]=3[C:29](=[O:39])[C:27]=2[N:28]=1>O1CCCC1.C(O)(=O)C>[OH:39][C:29]1([C:2]2[C:3](=[O:13])[NH:4][C:5](=[O:8])[NH:6][CH:7]=2)[C:27]2[N:28]=[C:24]([CH3:23])[O:25][C:26]=2[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:30]1=2
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: Cc1ccc2c(c1)CCc1oc(C)nc1C2=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a solution of the product from example 1 step (vi) (9 g) in dry tetrahydrafuran (100 ml) under nitrogen at −78° C. was added n-butyllithium (2.5M, 14.3 ml) dropwise over 1 min. After 30 min a warm solution of the product from step (v) (6.73 g) in tetrahydrofuran (350 ml) was added rapidly via cannula. After further stirring for 1 h the cooling bath was removed and the mixture allowed to stir at room temperature for 30 min. The reaction mixture was quenched with saturated brine and extracted with ethyl acetate (×2). The combined organic extracts were dried over magnesium sulphate and solvent removed under reduced pressure to leave a pale yellow foam. This was dissolved in acetic acid (100 ml) and stired at room temperature for 16 h. The solvent was evaporated under reduced pressure and the residue azeotroped with toluene (×2) to remove last traces of acetic acid. The remaining residue was triturated with diethyl ether/isohexane mixtures and filtered to give the subtitle product as a beige solid.
Reaction SMILES: [CH:1]([Si:4]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:7]2[CH:12]([CH2:13][OH:14])[CH2:11][O:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[O-:21]Cl=O.[Na+]>C(Cl)Cl.O>[CH:18]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:7]2[CH:12]([C:13]([OH:21])=[O:14])[CH2:11][O:10][C:8]=2[N:9]=1)([CH3:20])[CH3:19]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)[Si](c1nc2c(s1)C(CO)CO2)(C(C)C)C(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](c1nc2c(s1)C(C(=O)O)CO2)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A soln. of (2-(triisopropylsilyl)-5,6-dihydrofuro[2,3-d]thiazol-6-yl)methanol (1.77 g, 5.64 mmol)) in DCM (56 mL) was treated at 0° C. with DMP (2.87 g, 6.77 mmol) portionwise over 1 h. The mixture was stirred at 0° C. for 2 h, then, it was allowed to warm to RT and stirred for 2 h. Subsequently, the mixture was quenched with aq. sat. Na2S2O3 and aq. sat. NaHCO3 and was extracted with DCM. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was dissolved in tert-BuOH (16 mL) and 2-methyl-2-butene (4 mL) and treated at 0° C. dropwise over 30 min with a soln. of NaH2PO4 (2.64 g, 16.9 mmol) and NaClO2 (0.96 g, 8.46 mmol) in H2O (5 mL). The mixture was stirred at RT for 45 min, then, the volatiles were removed in vacuo, the residue was diluted with H2O and extracted with EtOAc. The comb. org. layers were dried over MgSO4 and conc. in vacuo.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:10]2[S:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][CH:14]=2)[S:6][C:7]=1[CH2:8][OH:9])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([C:10]2[S:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][CH:14]=2)[S:6][C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1cc(-c2ccc(-c3cccs3)s2)sc1CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(-c2ccc(-c3cccs3)s2)sc1CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
To a solution of 4-formyl-5-hydroxymethyl-2,2':5', 2"-terthiophene (0.1 g) in methanol (10 ml) was added excess amount of sodium borohydride. The reaction mixture was stirred at room temperature for 40 minutes. Methanol was removed and water was added. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give brownish solid product (0.1 g), melting point 99°-101° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br:17]Br>C(O)C.O1CCOCC1>[Br:17][CH2:2][C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)/C=C/c1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)/C=C/c1cccc(C(=O)CBr)c1
Reaction time: 1 h

Procedure:
10.9 g of ethyl (E)-3-(3-acetylphenyl)acrylate was dissolved in 50 ml of ethanol and 5 ml of dioxane. To the solution was dropwise added 8.8 g of bromine in 2 hours at 15° to 20° C. The mixture was stirred for 1 hour at the same temperature. The solvent was removed by distillation under reduced pressure to obtain ethyl (E)-3-[3-(2-bromoacetyl)phenyl]acrylate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].C1CN2C(=NCCC2)C1.O.Cl>CS(C)=O.C(O)C>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH:7]=[C:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: CCCC1=Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O

Procedure:
A solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid (1.2 g., 0.0033 mole) and 1,5-diazabicyclo [4.3.0]-5-nonene (0.8 ml.) in dimethylsulfoxide (8 ml.) is stirred at 25°C. for one hour then treated with water (30 ml.) hydrochloric acid (5 ml.) and ethanol (20 ml.) affording 4,5-dimethyl-6-oxo-7-propyl-6H-indeno[5,4-b]-furan-2-carboxylic acid as a red solid which melts at 242°C. after recrystallization from nitromethane.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=O)=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[NH2:42][C:43]1[CH:62]=[CH:61][C:46]2[N:47]([CH3:60])[C:48]([S:50][CH2:51][C:52]3[N:56]([CH2:57][CH2:58][CH3:59])[CH:55]=[N:54][CH:53]=3)=[N:49][C:45]=2[CH:44]=1>O1CCCC1.N1C=CC=CC=1.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:42][C:43]4[CH:62]=[CH:61][C:46]5[N:47]([CH3:60])[C:48]([S:50][CH2:51][C:52]6[N:56]([CH2:57][CH2:58][CH3:59])[CH:55]=[N:54][CH:53]=6)=[N:49][C:45]=5[CH:44]=4)=[O:31])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cncc1CSc1nc2cc(N)ccc2n1C
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4c(c2)nc(SCc2cncn2CCC)n4C)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (174 mg) in tetrahydrofuran (10 ml) was added one droplet of DMF. Then, thionyl chloride (0.038 ml) was added to the mixture, and the mixture was stirred for 1 hour under nitrogen atmosphere. This solution was slowly added dropwise to a solution of 5-amino-1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazole (120 mg) in pyridine (10 ml) at 0° C. under nitrogen atmosphere. The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazol-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (191 mg) (Compound 444) as yellow amorphous.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[N:3]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH:46]2[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48][CH2:47]2)=[C:39]2[C:43]=1[C:42](=[O:44])[N:41]([CH3:45])[CH2:40]2>>[OH:52][C@H:49]1[CH2:50][CH2:51][C@H:46]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:15][CH:14]=4)[N:3]=3)=[C:43]3[C:39]=2[CH2:40][N:41]([CH3:45])[C:42]3=[O:44])[CH2:47][CH2:48]1
Reactant: O=P(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Product: CN1Cc2c(c(Nc3nc(Nc4ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc4)ncc3C(F)(F)F)ccc2[C@H]2CC[C@H](O)CC2)C1=O

Procedure:
The title compound was prepared according to the procedure from Example 102 using bis(2,2,2-trifluoroethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 165A, 35.7 mg, 0.0671 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (18.5 mg, 0.0711 mmol). The crude material was first purified on a Teledyne/ISCO system eluting with 50-100% EtOAc:Heptane followed by MDP (under acidic conditions; formic acid). The desired fractions were collected and concentrated in vacuo, giving the title material as an off-white solid, 24.3 mg (47%, 0.0315 mmol). 1H NMR (400 MHz, DMSOd6) δ ppm 10.59 (br s, 1H), 9.93 (s, 1H), 8.47 (s, 1H), 8.15-9.25 (m, 1H), 7.63 (d, J=6.1 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (dd, J=8.6, 2.5 Hz, 2H), 4.58-4.72 (m, 5H), 4.53 (s, 2H), 3.43-3.61 (m, 3H), 3.08 (s, 3H), 1.94 (dd, J=11.7, 2.1 Hz, 2H), 1.77 (d, J=11.6 Hz, 2H), 1.56 (dtd, J=12.9, 12.7, 2.1 Hz, 2H), 1.21-1.37 (m, 2H). MS (ES+): m/z 756.16 (100) [MH+]. HPLC: tR=4.14 min (ZQ3, polar—5 min).