Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1.[Br:14][C:15]1[N:19]2[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.[F-].[K+].O>CS(C)=O.ClCCl>[Br:14][C:15]1[N:19]2[N:20]=[C:21]([N:10]3[CH2:11][CH2:12][CH2:13][CH:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Fc1ccc(F)c(C2CCCN2)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
In step 6A-4, 2-(2,5-difluorophenyl)pyrrolidine (6-5) (1.7 g, 9.3 mmol) was added to a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (11-1) (1.1 g, 230.92) and potassium fluoride (2.7 g, 46 mmol) in DMSO (10 mL). The resulting solution was heated to 130° C. and stirred over-night. The resulting dark orange slurry was cooled to room temperature, poured into 50 mL of DI water and extracted with ethyl acetate (3×150 mL). The ethyl acetate was dried with sodium sulfate and then removed to yield an orange solid. This solid was reconstituted with minimal amounts of dichloromethane (DCM) and purified using a silica gel column (40 g, ISCO) and a 0-5% gradient of methanol:DCM over a 20 minute period followed by 5% methanol for an additional 10 minutes. The solvent was removed from the desired fractions to yield 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) as a light yellow solid. m/z=379.2 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([N:31]=[C:32]=[S:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:22]=[C:23]([NH:31][C:32](=[S:33])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 52.7 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3,5-di(trifluoromethyl)phenyl isothiocyanate (1.08 g, 3.98 mmol) to afford the product (1.076 g); m.p. 192-193° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[C:25](=[O:28])[C:24]4[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].[ClH:39].N>CO.O>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[CH:25]([OH:28])[C:24]4[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4C(=O)C3=O)C2)cc1OC
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: COc1ccc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4C(O)C3=O)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.70 g (0.0014 mol) of 3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-yl)-methyl]-7, 8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-1,2-dione are dissolved in a mixture of methanol and water (95:5), 0.060 g (0.0016 mol) of sodium borohydride are added and the mixture is stirred for 20 minutes at ambient temperature. Then it is acidified with 2 molar hydrochloric acid, neutralized with ammonia and extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue obtained is purified over 100 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 15%). The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[C:17]([S:18][CH2:19][CH3:20])=[N:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:7][C:6]([C:21]([F:24])([F:23])[F:22])=[CH:5][N:4]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH2:19]([S:18][C:17]1[C:12]([C:10]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:21]([F:24])([F:23])[F:22])[CH:7]=[C:8]3[N:9]=2)=[N:13][CH:14]=[CH:15][N:16]=1)[CH3:20]
Reactant: CCSc1nccnc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCSc1nccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A mixture of 1.15 g of 3-ethylsulfanylpyrazine-2-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 1.23 g of p-toluenesolufonic acid-hydrate and 5 ml of NMP was heated and stirred at 150° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 631 mg of 2-(3-ethylsulfanylpyrazin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 6).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCC(CCCCN)CCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C

Procedure:
To a solution of 2200 g of crude ethyl 8-amino-4-[3-(3-pyridyl)-propyl]-octanoate in 28.8 L of dichloromethane is added 1377 g of triethylamine. The solution is cooled to 0° and a solution of 1435 g of p-chlorophenylsulfonyl chloride in 14.3 L of dichloromethane is added over a period of 45 minutes maintaining the temperature below 5°. The reaction is allowed to slowly warm up to room temperature overnight. The reaction mixture is washed 3 times with 15 L of sodium bicarbonate and then with water, dried over sodium sulfate and evaporated to dryness to yield ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-propyl]-octanoate as an oil.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]2)=[CH:5][C:4]=1[F:20].[OH:23][CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=2)[S:28][CH:29]=1>>[OH:23][CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:3]3[CH:8]=[CH:7][C:6]([N:9]4[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]4)=[CH:5][C:4]=3[F:20])=[CH:34][CH:35]=2)[S:28][CH:29]=1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Reactant: OCc1csc(-c2ccc(Br)cc2)n1
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(-c4nc(CO)cs4)cc3)c(F)c2)CO1

Procedure:
With the exception of using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material and 4-(4-hydroxymethylthiazol-2-yl)-bromobenzene, the same procedure as in Example 1 was conducted to prepare the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(C=O)cc1Oc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cc1Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of 3-(3-chloro-phenoxy)-4-methoxy-benzaldehyde (12) (393 mg, 1.5 mmol) in methanol (5 ml) was added sodium borohydride (300 mg, 7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice-water, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. The solvent was removed under vacuum to yield 330 mg (85% yield) of compound (13).
Reaction SMILES: [CH3:1][N:2]([C@@H:11]([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=O)[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])=[O:4].CCN=C=NCCC[N+](C)(C)C.[I-].ON1C2C=CC=CC=2N=N1.[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH2:69])[CH2:60][C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[C:63]([Cl:68])[CH:62]=2)[CH2:46]1)[CH:42]=[CH2:43]>C(N(CC)CC)C.CN(C)C=O>[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH:69][C:12](=[O:14])[C@@H:11]([N:2]([CH3:1])[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:4])=[O:5])[CH2:15][CH:16]=[CH2:17])[CH2:60][C:61]2[CH:62]=[C:63]([Cl:68])[CH:64]=[C:65]([Cl:67])[CH:66]=2)[CH2:46]1)[CH:42]=[CH2:43]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(Cl)cc(Cl)c2)c2cc(OC)ccc21
Reactant: C=CC[C@@H](C(=O)O)N(C)S(=O)(=O)CCCCC
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(Cl)cc(Cl)c2)NC(=O)[C@H](CC=C)N(C)S(=O)(=O)CCCCC)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
Step DL (1): A mixture of 28.7 mg (S)-2-(N-methylpentylsulfonamido)pent-4-enoic acid (0.11 mmol, from Preparation J), 24.8 mg 1-[3-(dimethyamino)propyl]-3-ethyl carbodiimide methiodide (0.083 mmol), 18 mg 1-hydroxybenzotriazole, 3 drops triethylamine and 1 mL dimethyl-formamide was stirred for 15 minutes at rt. The mixture was then added to 21 mg (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (0.046 mmoles, from Preparation BG) and the reaction mixture was allowed to stand at rt overnight. The reaction mixture was subjected to preparative HPLC, with the peak at 9.8 min collected to yield 14.1 mg (S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl-amino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(N-methylpentyl-sulfon-amido)pent-4-enamide as a clear oil. LC-MS Rt 2.18 min (method A), (M+H)+=696.0, 698.0; HRMS (M+H)+=696.2653; 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=8.2, 1H) 7.19 (s, 1H) 7.14 (s, 2H) 6.94 (d, J=2.1, 1H) 6.84 (d of d, J=8.2, 2.4, 1H) 6.68 (d, J=9.1, 1H) 5.95 (m, 1H) 5.69 (m, 1H) 5.31 (d, J=17, 1H) 5.2-5.08 (m, 3H) 4.77 (t, J=5.5, 1H) 4.17 (d of d, J=9.5, 5.7, 1H) 4.10 (m, 1H) 3.80 (s, 3H) 3.51 (m, 1H) 3.12 (d of d, J=14.3, 3.7, 1H) 2.90 (m, 4H) 2.67 (m, 4H) 2.54 (s, 3H) 2.31 (m, 2H) 1.93 (d, J=13.4 of t, J=4.6, 1H) 1.75 (m, 2H) 1.33 (m, 4H) 0.90 (t, J=7, 3H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)C>[OH-].[Na+].C(O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)COc1ccc(OCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(OCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of {4-[3,3-bis-(4-chloro-phenyl)-allyloxy]-phenoxy}-acetic acid ethyl ester (140 mg, 0.3 mmol) in 1N NaOH (1 ml) and ethanol (10 ml) was stirred at room temperature for 18 hours. The reaxtion mixture was evaporated and the residue dissolved in water (5 ml) and 1 N HCl (1.2 ml). The aquous phase was extracted with ethyl acetate (3×15 ml), dried (MgSO4) and evaporated to give the title compound in 130 mg (99%) yield.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])(=[O:44])=[O:43])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Yield: 82 %

Procedure:
Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate (0.06 g, 0.1 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.06 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoic acid as an off-white solid; mp 132–135° C.; MS (ESI) m/z 729.74 ((M−H)−); HRMS: calcd for C39H33Cl2FN2O5S, 730.1471; found (ESI+), 731.15514.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C@@H:14]([CH3:18])[C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=2[N:24]=1.[CH3:33][NH:34][CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:33][N:34]([CH3:35])[C:15]([C@@H:14]([NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:18])=[O:16]
Reactant: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C)C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C)C(=O)N(C)C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide (25 mg) was prepared by following General Procedure F starting from (S)-2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (100 mg), dimethylamine (119 uL, 2 M in THF), HBTU (98 mg), and DIEA (57 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 490.6. 1H NMR (DMSO-d6, 400 MHz): δ 8.56 (d, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.84 (d, 1H), 7.71 (d, 2H), 7.53 (d, 1H), 5.00-4.87 (m, 1H), 3.70 (s, 3H), 3.07 (s, 3H), 2.86 (s, 3H), 1.32 (d, 3H), —NH proton signal was not observed.
Reaction SMILES: CN(OC)[C:3](=[O:6])[CH2:4][F:5].[Li][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>>[F:5][CH2:4][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:6]
Reactant: CON(C)C(=O)CF
Reactant: [Li]c1cccnc1
Product: O=C(CF)c1cccnc1

Procedure:
N-Methyl-N-methoxyfluoroacetamide (D6) (12.64 g, 0.104 mol) was treated with 3-lithiopyridine as in the method of Description 7 to afford 3-(α-fluoroacetyl)pyridine (9.63 g). This crude material was taken-up in dry methanol (100 ml) and treated with methoxylamine hydrochloride (6.63 g, 0.076 mol) at reflux for 1 h. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous potassium carbonate (100 ml) and chloroform (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in ether and insoluble material was removed by filtration. The solvent was removed in vacuo and the residue was distilled to afford the title compound (D9) as an oil (10.22 g, 58%) b.p. 110° C. at 0.5 mmHg (Kugelrohr), which consisted of a 4:1 mixture of Z and E isomers.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.Cl.C(=O)(O)[O-].[Na+]>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:25][CH2:24][C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)=[N:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: NCc1ccncc1
Reactant: CCCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCn1c(=S)nc(NCc2ccncc2)c2[nH]c(C3CC3)nc21

Procedure:
5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6-dithioxanthine and 21.3 ml (200 mmoles) of 95% 4-picolylamine were heated under argon to 150-5° C. After 14 hours the cooled solution was poured into 100 ml of water, acidified with 19 ml of 10N HCl and 1N HCl to pH 6, where an orange colored gum was formed. With sodium bicarbonate the mixture was neutralized to pH 7. With time the gum crystallized and the solid is collected and washed. The residue was suspended in acetone and the crystals collected: 3.92 (57.6%) of crude product. The filtrate was evaporated to dryness, dissolved in 40 ml of 0.5N NaOH, extracted 4 times with methylenechloride, and acidified again with 5N HCl to pH 6. Again the gum crystallized over 48 hours and the mixture was neutralized to pH 7 with bicarbonate and the solid collected: 1.75 g (25.7%) of crude product. Both parts were dissolved in 30 ml of methylenechloride and filtered through 30 g of silicagel in a column. 150 mg (2.8%) of starting material was recovered first, then 5.04 g (74.0%) of product was recovered with 5% of methanol, which was dissolved in 32 ml of 1N HCl, treated with 250 mg of charcoal, filtered, and neutralized with 7.5 ml of 2N NaOH and sodium bicarbonate solution to pH 7-8. The water phase was decanted from the gum and the latter washed with water and crystallized from acetone: 4.08 g (59.9%) of thioisoguanine with mp 204-210° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH:27]=[CH:26][CH2:25][O:24]1)[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: C[C@H](NC(=O)c1ccc(N2CC=CCO2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1ccc(N2CCCCO2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
209 mg (0.50 mmol) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide together with 100 mg 10% palladium charcoal in 5 ml of ethyl acetate for 7 minutes are hydrogenated at ambient temperature at 5 bar under a hydrogen atmosphere. Then the mixture is suction filtered, the filtrate is evaporated down i. vac. and evaporated again with ether.
Reaction SMILES: C[Si](Cl)(C)C.C(=O)([O:12][C:13]1[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:23]([CH3:26])([CH3:25])[CH3:24])OC(C)(C)C.[N+:28]([O-])([O-:30])=[O:29].[K+].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[C:23]([C:14]1[C:15]([N+:28]([O-:30])=[O:29])=[CH:16][CH:17]=[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:12])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Oc1c(C(C)(C)C)cccc1C(C)(C)C
Reactant: O=[N+]([O-])[O-]
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc([N+](=O)[O-])c(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
TMSCl (8.5 g, 78.24 mmol) and tert-butyl (2,6-di-tert-butylphenyl) carbonate (12.0 g, 39.16 mmol) was added to a suspension of KNO3 (5.9 g, 58.36 mmol) in CHCl3 (100 mL) successively at 0° C. The reaction mixture was stirred for 0.5 h and AlCl3 (15.5 g, 116.20 mmol) was added. The stirring was continued for 2 h and the resulting mixture was poured into ice-water and extracted with CH2Cl2. The combined organic layers were washed with sat. NaHCO3 solution and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether) to give 2,6-di-tert-butyl-3-nitrophenol (2.5 g, 25%). 1H NMR (300 MHz, CDCl3) δ 7.18 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 5.57 (s, 1H), 1.51 (s, 9H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[OH:28].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:28][C:21]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=1[Cl:19]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)c(Cl)cc2Cl)c(Cl)c1Oc1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 28.4 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 21.6 gm of 2,4,5-trichloro-phenol, 10 ml of 10 N sodium hydroxide and 80 ml of dimethylsulfoxide was stirred for 6 hours at 100° C. Thereafter, the reaction mixture was admixed with 600 ml of 1 N sodium hydroxide, and the precipitated product was collected by suction filtration and recrystallized from 150 ml of ethanol. 31 gm (77.4% of theory) of the title compound, m.p. 112° C., were obtained. An additional amount of the product (about 6 gm) was obtained by evaporating the filtrate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[CH:8]1[O:12][CH2:11][CH2:10][CH2:9]1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:31][O:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[C:23]=2[C:22]2[CH:21]=[C:20]([OH:35])[CH:19]=[CH:18][C:17]=2[N:16]=1.[Cl-].[Na+]>CN(C=O)C.O>[CH2:33]([O:32][CH2:31][C:26]1[N:27]([CH2:28][CH2:29][CH3:30])[C:23]2[C:22]3[CH:21]=[C:20]([O:35][CH2:7][CH:8]4[CH2:9][CH2:10][CH2:11][O:12]4)[CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:14])[C:24]=2[N:25]=1)[CH3:34]
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCC4CCCO4)cc3c21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of tetrahydrofurfuryl bromide (330 mg, 1.99 mmol) and 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500 mg, 1.66 mmol, prepared in Parts A and B of Example 566) in anhydrous DMF (20 mL). The reaction mixture was heated at 75° C. overnight, allowed to cool, and poured into deionized water (300 mL). After 30 minutes of stirring, a brown precipitate formed. Sodium chloride (100 g) was added, and the resulting mixture was stirred for three hours and then filtered. The isolated precipitate was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-35% methanol/dichloromethane (10:90) in dichloromethane). The resulting solid was recrystallized from acetonitrile and dried under high vacuum to yield 429 mg of 2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-2-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amine as a fluffy, white solid, mp 178-179° C. Anal. calcd for C21H28N4O3.0.25H2O: C, 64.84; H, 7.39; N, 14.40. Found: C, 65.03; H, 7.75; N, 14.48.