Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[CH3:13][O:14][C:15]([C:17]1([CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: BrCCCCBr
Reactant: COC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCCCBr)CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 1, starting from diisopropylamine (21 mL, 150 mmol), n-butyllithium (58 mL, 145 mmol), cyclopentanecarboxylic acid methyl ester (13.1 g, 100 mmol), and 1,4-dibromobutane (21.59 g, 100 mmol), and after distillation, resulted in a colorless oil (12.8 g, 48%). ES(+)-HRMS m/e calcd. for C11H19BrO2 (M+H)+ 262.0568, obsd. 262.0565.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>>[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1
Reactant: Cc1cccc(CBr)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Solvent: NCc1ccccc1
Product: Cc1cccc(CN2CCC(COc3cccc4nc(N)nc(N)c34)CC2)c1
Yield: 84 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 3-methylbenzyl bromide (60 mg; 0.32 mmol) via Method BB to yield 86 mg. (84% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.34 (t, J=8.0 Hz, 1H), 7.2 (m, 3H), 7.07 (m, 3H), 6.76 (d, J=8.4 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 3.98 (d, J=6.0 Hz, 2H), 3.42 (s, 2H), 2.83 (br d, J=11.2 Hz, 2H), 2.29 (s, 3H), 1.8 (m, 5H), 1.36 (m, 2H). MS m/z (ESI) 378 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C.CO>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: NC(=O)NC1CCC(O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 2.5 liters of ethanol, 34.85 grams of (-)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is stirred and 9.8 grams of NaBH4 is added. The mixture is stirred overnight at room temperature, 1400 ml. of water is added, and after stirring for 0.5 hour the ethanol is evaporated in vacuo. The mixture is cooled and 25-30 ml. of acetic acid is added until no more foaming occurs. The mixture is stirred for 0.75 hour, filtered to collect the first crop and this solid is washed with water and air dried. This solid is recrystallized from acetone and then from acetone/methanol to give 6.75 g. of isomer B of the title compound, m.p. 211°-213° C. (dec.), [α]D25.5 =-23.23° (c, 3.11 in methanol). This material contains 92% isomer B and 8% isomer A when assayed by high pressure liquid chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14].C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:9]([CH3:10])[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14]
Reactant: CNCc1cccc(Br)c1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)c1ccc2ccccc2c1)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.9 %

Procedure:
To a solution of Compound 14 (23.1 g, 115.5 mmol) in methylene chloride (500 mL) was added α-bromo-2′-acetonapthone (27.9 g, 110.0 mmol) and the resulting mixture was stirred at 0° C. for 1 h prior to the addition of triethylamine (15.3 mL, 47.4 mmol). The reaction mixture was stirred at 0° C. for 2 h. The resulting mixture was diluted with water (200 mL) and the aqueous phase was extracted with additional methylene chloride (2×200 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to afford Compound 15 (44.5 g) as a light yellow oil, which was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ 8.49 (s, 1H), 8.01 (dd, J=8.8, 1.8 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.90-7.84 (m, 2H), 7.62-7.52 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 3.91 (s, 2H), 3.68 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH:14]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11])=[CH:4][CH:3]=1
Reactant: COC(C=O)OC
Reactant: NCCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CNCCc1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of 4-fluorophenethylamine (2.00 mL, 15.0 mmol) and dimethoxyacetaldehyde (60% solution in water, 2.53 mL, 16.83 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (4.28 g, 20.20 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography eluted with ethyl acetate/hexane to afford N-(4-fluorophenethyl)-2,2-dimethoxyethanamine as a colorless oil in 52% yield (1.78 g): 1H NMR (300 MHz, CDCl3) δ 7.14-7.10 (m, 2H), 6.97-6.91 (m, 2H), 4.43-4.40 (m, 1H), 3.35 (s, 6H), 2.89-2.81 (m, 2H), 2.76-2.71 (m, 4H); MS (ES+) m/z 228.2 (M+1).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:25][C:26]([NH2:28])=[S:27])[CH2:23][CH3:24]>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:28]=[C:26]([NH:25][CH2:22][CH2:23][CH3:24])[S:27][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCCNC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Product: CCCNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (0.346 g, 0.932 mmol) (Example 26, Step 2) in ethanol (15 mL) in a 25 mL round bottom flask was added N-propylthiourea (0.116 g, 0.979 mmol) with stirring. The resulting solution was heated to reflux for 24 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride, washed successively with Na2CO3 (10% solution) and brine, dried over Na2SO4, filtered and reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino) thiazole as a yellow crystalline solid (0.276 g, 76%): mp 181°-182° C. 1H NMR (DMSO-d6) 400 mHz 5 7.97 (t, J=5.37 Hz, 1H), 7.78 (d, J=8.79 Hz, H), 7.42 (dd, J=5.86, 8.79, 2H), 7.37 (d, J=8.79, H), 7.15 (t, J=8.79 Hz, 2H), 3.21 (q, J=6.84, H), 3.18 (s, 3H), 1.60 (m, 2H), 0.91 (t, J=7.33, H). MS (EI): m/z 390 (M+). HRMS Δ=2.4 mmu.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:34]([CH:31]4[CH2:33][CH2:32]4)[CH:35]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cccc(C2CC2)c1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C4CC4)c3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 35.6 %

Procedure:
The title compound was prepared by following the same procedure as described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 3-cyclopropyl aniline (0.079 g, 0.598 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.070 g of the desired product. 1HNMR (DMSO-d6): δ 0.66 (d, J=4.8 Hz, 2H), 0.93 (d, J=2.1 Hz, 2H), 1.57 (s, 6H), 1.92 (m, 1H), 3.10 (s, 2H), 6.77 (d, J=7.8 Hz, 1H), 7.18-7.48 (m, 7H), 9.69 (s, 1H), 11.13 (s, 2H); MS [M]+: 491.30.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].C(OC)(=O)C.[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([CH2:20][C:21]#[N:22])=[O:19])=[CH:16][CH:15]=1.Cl>CO.N1C=CC=CC=1>[CH2:1]([S:4]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH2:20][C:21]#[N:22])=[O:19])=[CH:23][CH:24]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: N#CCC(=O)c1ccc(N)cc1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: COC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(C(=O)CC#N)cc1
Temperature: 0 °C

Procedure:
Dry pyridine (13 ml) was added dropwise to a stirred mixture of 14.3 g (0.1 mole) 1-propanesulfonyl chloride, 15 ml dry methyl acetate and 16.0 g (0.1 mole) 4-aminobenzoylacetonitrile at room temperature. An ice bath was then used to control the exothermic reaction and the mixture was stirred in the ice bath for two hours. Methanol (50 ml) was added and the resulting solution poured into 2 N hydrochloric acid (240 ml) with stirring. The solid was collected, washed with water and dried. Yield 20.7 g (78%). Recrystallization yielded product melting at 150°-151° C.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH3:15])=O)(=[O:3])[CH3:2].CC([O-])=O.[K+].Cl.[O:23]([NH2:25])[CH3:24]>CCO.O>[C:1]([O:4][CH:5]([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH3:15])=[N:25][O:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)C(=O)c1ccc(Br)cc1C
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CON=C(c1ccc(Br)cc1C)C(C)OC(C)=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a mixture of 2-(4-bromo-2-methylphenyl)-1-methyl-2-oxoethyl acetate (5.0 g, 17.5 mmol) and KOAc (2.75 g, 28.0 mmol) in EtOH (90 mL) was added methoxylamine hydrochloride (2.34 g, 28.0 mmol) and the resulting milky suspension was stirred at 70° C. for 4 h. An additional 0.5 equivalents of KOAc and methoxylamine hydrochloride were added and the reaction mixture was stirred at 70° C. for 8 h. The reaction mixture was diluted with water, and the EtOH was removed under reduced pressure. The aqueous residue was extracted with diethyl ether (2×75 mL), and the ether extracts were combined, washed with aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give 2-(4-bromo-2-methylphenyl)-2-(methoxyimino)-1-methylethyl acetate (5.0 g, 91%) as a racemic mixture of the E- and Z-methoxime isomers as a gold oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(Oc2ccccc2C=O)cc1
Yield: 77 %

Procedure:
Preparation analogous to Example 12 a) from 2-fluoro-benzaldehyde and 4-tert-butylphenol. Yield: 77%, yellow oil after high vacuum distillation (93°-100° C., 0.9 mbar); TLC (silica gel; hexane/ethyl acetate=1:1; UV): Rf =0.65; 1H-NMR (CDCl3, 200 MHz): 1.35 (s, 9H); 6.75-7.55 (m, 7H); 7.92 (dd, 1H); 10.50 (s, 1H); MS: 254 (M+), 239.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]([Cl:30])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:21]C)=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]([Cl:30])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[C:9]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-(4-fluoro-benzenesulfonyl)-benzene (468 mg, 0.99 mmol) in CH2Cl2 (8 mL) was added boron tribromide (1M in CH2Cl2, 2.0 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 2 h and quenched with water (50 mL). After stirring at room temperature for 1 h, the solution was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried and concentrated to yield the title compound of Step B (454 mg). The title product of Step B was used in the next step without purification. MS (APCl−) Calc.: 457.0. Found: 456.0 (M−1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1)=O)(C)(C)C.O>COCCO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:31][C:29]4[CH:30]=[N:26][NH:27][CH:28]=4)[N:3]=[CH:4][C:5]=3[N:10]=[N:9]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Solvent: COCCO
Solvent: O
Product: COc1ccc(-n2nnc3cnc(Nc4cn[nH]c4)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 262 mg (1.00 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 183 mg (1.00 mmol) 4-amino-pyrazole-1-carboxylic acid tert-butyl ester in 2.5 ml 2-methoxy-ethanol is stirred for 3 hours at 100° C. The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off, washed with water and dried. The crude product is recrystallized from isopropanol giving “A3” as brown crystals; HPLC/MS (A): 1.6 min, [M+H] 309;
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[NH:14][C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:25](I)[CH3:26]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[N:14]([CH2:25][CH3:26])[C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(C)cc3c2=O)CC1
Reactant: CCI
Product: CCOC(=O)N1CCC(n2c(=O)c3cc(C)ccc3n(CC)c2=O)CC1
Yield: 79 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 1.0 g (3.02 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound f) was used in place of Compound 24 and ethyl iodide was used in place of methyl iodide, whereby 855.0 mg (yield: 79%) of Compound b was obtained as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18]CC)=[O:17].N1C=CC=CC=1S(NC1C=C(C=CC=1)C(O)=O)(=O)=O>>[CH3:1][C:2]1[N:7]=[C:6]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)n1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Product: Cc1cccc(S(=O)(=O)Nc2cccc(C(=O)O)c2)n1
Yield: 94 %

Procedure:
Intermediate 5b (solid) is prepared using intermediate 4c and ethyl 3-aminobenzoate using the procedure described for 5a.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][C:10]=1[Br:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(N)sc1Br
Reaction time: 3 h

Procedure:
2-Amino-thiazole-4-carboxylic acid ethyl ester (1.4 g, 8 mmol) is dissolved in acetonitrile (15 ml) and N-bromosuccinimide. (1.7 g, 9.6 mmol, 1.2 equiv.) was added in one portion. The mixture was stirred at room temp. for 3 hours, then filtered and the filtrate was evaporated. After purification on silica-gel with ethyl acetate/n-heptane as eluent, 0.71 g of an off-white solid were obtained: MS: m/e 248.9 (M−H).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[C:20]([Br:28])[CH:19]=1>C(O)(=O)C>[Br:28][C:20]1[C:21]([OH:27])=[C:22]([C:23]([OH:25])=[O:24])[CH:26]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=1
Reactant: Nc1cc(Br)c(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)cc(Br)c1O

Procedure:
A mixture of 8.1 g. (0.038 mole) of 2-phenacylcyclohexanone, 8.7 g. (0.038 mole) of 5-amino-3-bromosalicylic acid, and 50 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled and filtered. Recrystallization of the collected solid from acetonitrile gave 7.0 g. (46%) of yellow crystals, m.p. 209°-210°.
Reaction SMILES: [CH3:1][C:2]([CH3:60])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:57])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:56])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[C:41](\[CH3:55])/[C:42]([NH:44][C:45]4([C:48]5[N:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=5)[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:59])[CH3:58])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.CC#N.O>C(Cl)Cl>[Cl:54][C:51]1[CH:52]=[N:53][C:48]([C:45]2([NH:44][C:42](=[O:43])/[C:41](/[CH3:55])=[CH:40]/[C@:23]34[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]3[C@@H:25]3[C@@:20]([CH3:56])([CH2:21][CH2:22]4)[C@@:19]4([CH3:57])[C@@H:28]([C@:29]5([CH3:32])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:58])([CH3:59])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:60])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)[CH2:47][CH2:46]2)=[N:49][CH:50]=1
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ncc(Cl)cn2)CC1
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ncc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(5-chloropyrimidin-2-yl)cyclopropyl)amino)-2-methyl-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (250 mg, 0.295 mmol) in DCM (6 mL) was added TFA (3 mL, 0.295 mmol). The reaction mixture was stirred at rt for 2 hr and evaporated in vacuo to afford crude product. This material was diluted with DCM (30 mL), and washed with water, saturated NaHCO3, water, saturated NH4CI and water. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a residue which was dissolved into MeCN—H2O (1:2, 9 mL) and freeze-dried to give the title compound (120 mg, 0.149 mmol, 50.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.22 (br. s., 1H), 8.75 (s, 2H), 8.60 (s, 1H), 6.57 (s, 1H), 4.39 (dd, J=4.8, 11.3 Hz, 1H), 3.24-3.10 (m, 1H), 2.82-0.59 (m, 57H); LC/MS: m/z calculated 789.5. Found 790.3 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:5].C(N(CC)CC)C.[C:44](Cl)(=O)[O:45]C(Cl)(Cl)Cl>O1CCCC1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][N:22]1[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]=[C:18]1[CH2:17][CH:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:1][C:44]2=[O:45])[CH2:16][CH2:15]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1C(=O)NCCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred mixture of 3.88 parts of 2-amino-N-[4-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]benzamide, 2 parts of N,N-diethylethanamine and 90 parts of tetrahydrofuran were added dropwise 1.64 parts of trichloromethyl carbonochloridate. Upon completion, stirring was continued overnight. Another portion of 1.6 parts of B was added and the whole was stirred ovrnight. The precipitate was filtered off and the filtrate was evaporated. Water was added to the residue. The solution was treated with ammonium hydroxide; The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3 parts (73%) of 3-[4-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione; mp. 185.5° C. (490).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)CN
Reactant: O=Cc1ccc2c(c1)OCCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CNCc1ccc2c(c1)OCCCO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cold mixture of 15 g of 3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde and 67 mL (8 equiv) of isobutylamine in 100 mL of 1,2-dichloroethane was added 50 mL (10 equiv) of acetic acid and 25 g (1.4 equiv) of sodium triacetoxyborohydride. The mixture was allowed to warm and stir overnight then diluted with 500 mL of chloroform and washed with 500 mL of 5N NaOH. The aqueous layer was extracted with 4 additional 100 mL portions of chloroform and the combined extracts dried over magnesium sulfate and concentrated under reduced pressure. After drying under vacuum the product was obtained as clear oil: MS (m+1)=236.2; 1H NMR (400 MHz, CDCl3) 7.0-6.8 (m, 3H), 4.2 (q, 4H), 3.65 (s, 2H), 2.42 (d, 2H), 2.2 (m, 2H), 1.8 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(O)CCBr
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(O)CCN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (7 mL), sodium tert-butoxide (153 mg, 1.588 mmol) and 4-bromo-2-methylbutan-2-ol (243 mg, 1.456 mmol) (306 mg, 74%). ESI-MS m/z [M+H]+ calc'd for C14H21ClN4O2, 313.14; found 313.2.