Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])[N:35]=[CH:34][C:33]=1[NH2:45].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:43])([CH3:44])[C:39]([F:40])([F:41])[F:42])[N:35]=[CH:34][C:33]=1[NH:45][C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[CH:6]=[N:7][C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[CH:21][C:22]=1[F:30]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: CC(C)(c1cc(Br)c(N)cn1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)C(F)(F)F)cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (30 mg, 0.073 mmol) in pyridine (5 mL) was added 4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine (20.64 mg, 0.073 mmol) and T3P® (EA solvate) (0.5 mL, 0.073 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated and purified by preparative TLC (DCM/MeOH=15:1, Rf=0.6) to yield a light yellow solid of N-(4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.038 mmol, 51.7% yield): 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.33 (d, J=9.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.48 (s, 1H), 5.30 (s, 2H), 4.16 (q, J=6.8 Hz, 2H), 3.93 (s, 2H), 3.82 (s, 3H), 1.63 (s, 6H), 1.40 (t, J=7.0 Hz, 3H). ES-LCMS m/z 678.0 (M+H+2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH2:35]Cl)[CH:34]=1.O>C(#N)C>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:32]=[N:31][CH:30]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 5 h

Procedure:
171 mg (0.56 mmol) of the compound from Example 5A and 543 mg (1.67 mmol) of cesium carbonate were dissolved in 11 ml of acetonitrile, and 135 mg (0.56 mmol) of 3-bromo-5-(chloromethyl)pyridine hydrochloride were added. The mixture was stirred at 65° C. for 5 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 102 mg (38% of theory) of the target compound.
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[OH-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>O.[Cl-].[Na+].O>[Na+:1].[Cl:13][C:4]1[CH:5]=[C:6]([S:9]([O-:12])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=1[O:2][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)([O-])c1ccc(O)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
4-hydroxy-3-chlorobenzenesulfonic acid sodium salt (11.53 g, 50.0 mmol) and sodium hydroxide (2.00 g, 50.0 mmol) were dissolved in distilled water (50 mL) and the solution cooled to 0° C. Methane sulfonyl chloride (4.25 mL, 55.0 mmol) was added dropwise with stirring and the mixture then allowed to warm to room temp. and left for 2 h. Brine (20 mL) was added and the solution left to stand for 1 h with the formation of white crystalline solid. The solids were filtered, recrystallised (brine), and dried under vacuum to give the title compound as a white crystalline solid (9.40 g, 61%),
Reaction SMILES: [SH:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][CH2:19][CH2:20][CH2:21]Br.Cl>CN(C)C=O>[F:18][CH2:19][CH2:20][CH2:21][S:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:9])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ncccc1S
Reactant: FCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ncccc1SCCCF
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
A mixture consisting of 0.285 g of 3-mercaptopyridin-2-ylsulfonamide, 0.455 g of potassium carbonate, 5 ml of dry dimethylformamide and 0.23 g of 3-fluoro-1-bromopropane is stirred for 90 minutes at a temperature of +25° C. in a nitrogen atmosphere. The reaction mixture is subsequently added to an ice/water mixture. After a pH of 2 has been established with 2.8 ml of 2N HCl, the reaction mixture is extracted twice with ethyl acetate. The combined organic phases are washed three times with water and subsequently dried over sodium sulfate. Concentration and subsequent chromatographic purification of the residue over silica gel with ethyl acetate/n-hexane (1:1 ) give 0.12 g of 3-(3-fluoropropythio)pyridin-2-ylsulfonamide of a melting point of 85° to +86° C.
Reaction SMILES: C([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)C1C=CC=CC=1.C(N([CH2:38][CH3:39])C(F)(F)C(Cl)F)C>>[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][C@H:13]([CH:38]=[CH2:39])[C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1
Reactant: C[C@]12CC[C@H](OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCN(CC)C(F)(F)C(F)Cl
Product: C=C[C@H]1C=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
Reaction of 3β,16α-dihydroxyandrost-5-en-17-one 3β-acetate 1 with a fluorinating agent such as diethyl (2-chloro-1,1,2-trifluoroethyl)amine affords 16α-fluoro-3β-hydroxyandrost-5-en-17-one 3-acetate 3. Hydrolysis of the ester with aqueous acid yields 16α-fluoro-3β-hydroxyandrost-5-en-17-one, 2a. ##STR47##
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C([O:11]/[C:12](/[C:22](OC)=[O:23])=[C:13](/OC(=O)C)\[C:14]([O:16][CH3:17])=[O:15])(=O)C.C(OC(C)C)(C)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH3:17][O:16][C:14]([C:13]1[N:7]=[C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]2[C:22](=[O:23])[C:12]=1[OH:11])=[O:15]
Reactant: Cc1cc(N)no1
Reactant: COC(=O)/C(OC(C)=O)=C(\OC(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COC(=O)c1nc2cc(C)on2c(=O)c1O
Temperature: 100 °C
Yield: 37 %

Procedure:
5-Methyl-isoxazol-3-ylamine (392 mg, 3.99 mmol), dimethyl diacetoxyfumarate (1.04 g, 3.99 mmol) and p-toluenesulphonic acid (10 mg) were combined in a capped vial and heated to 100° C. After 5 h the reaction was cooled to room temperature and ethanol (2.5 mL) and iso-propyl ether (2.5 mL) was added to the residue which was sonicated for 15 min. The resulting precipitate collected by filtration and washed with cold ethanol (5 mL) and dried on the pump to afford 6-hydroxy-2-methyl-7-oxo-7H-isoxazolo[2,3-α]pyrimidine-5-carboxylic acid methyl ester (331 mg, 37%): 1H NMR (300 MHz, D6DMSO) δ 2.50 (3H, s, CH3), 3.84 (3H, s, OCH3), 6.67 (1H, s, H3), 10.31 (1H, br s, OH).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:33])[C:26](=[CH:31][CH:32]=1)[C:27](OC)=[O:28]>>[OH:33][C:25]1[CH:24]=[C:23]([O:22][CH3:21])[CH:32]=[CH:31][C:26]=1[C:27](=[O:28])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1

Procedure:
Prepared according to above procedure using diisopropylamine (8.0 mL, 58 mmol), nBuLi (34 mL, 1.6 M), tert-butyl acetate (4.7 mL, 35 mmol), methyl 4-methoxysalicylate (1.83 g, 10 mmol) yielding 2.04 g (76%) as white needles. mp=40-42° C.; IR (film) 2978.7; 2936.4; 1731.9; 1633.5; 1357.0; 1129.3 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.42 (s, 1H); 7.57 (d, J=9.0 Hz, 1H); 6.45 (d, J=9.0, 1H); 6.44 (s, 1H); 3.85 (s, 3H); 3.84 (s, 2H); 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 197.1, 166.7, 166.6, 165.9, 132.3, 113.5, 108.3, 101.2, 82.5, 55.9, 47.2, 28.2; LRMS (electrospray): Mass calculated for C14H18O5, [M]+, 266.12. Found [M+23]+, 289.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1>>[F:18][C:15]1[CH:14]=[N:13][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:17][CH:16]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: OB(O)c1ccc(O)cc1
Product: Oc1ccc(-c2ncc(F)cn2)cc1
Yield: 42 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-hydroxybenzene boronic acid and 2-chloro-5-fluoro-pyrimidine to afford the title compound as a white solid (575 mg, 42%)
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:44]5[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:42][CH2:43]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccc(Cl)c(Cl)c3)C4)cc2)CC1

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and 1-(2-methoxyethyl piperazine was used instead of piperidine to give 6-(3,4-dichlorophenyl)-N-(4-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine M.p.=121-122° C. 1H NMR 400 MHz (CDCl3) δ 12.75 (br s, 3H), 11.8 (s, 1H), 8.37 (br s, 1H), 7.98 (br s, 1H), 7.76 (br s, 2H), 7.60 (m, 2H), 7.36-7.27 (m, 1H), 7.18 (s, 1H), 7.10 (d, J=7.1 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.37 (br s,1H), 4.0-3.6 (br s,8H), 3.45-3.0 (m, 8H), 2.72 (s, 3H). LCMS m/e 588 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH2:38]O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24](=[O:40])[C:25]1[CH:26]=[CH:27][C:28]([CH:31]([CH2:38][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:30]=1
Reactant: CCCCCCC(CO)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4′-trifluoromethyl-biphenyl-4-ol (213 mg, 0.90 mmol) and 3-[4-(1-hydroxymethyl-heptyl)-benzoylamino]-propionic acid methyl ester (240 mg, 0.72 mmol) in anhydrous toluene (5 mL) is degassed and filled with nitrogen 3 times. Tributylphosphine (270 μL, 1.07 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (271 mg, 1.07 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is loaded on a silica gel column and purified using hexanes/ethyl acetate. Some racemic ester is hydrolyzed in the next step, and the remaining intermediate ester is sent to chiral chromatography for resolution (see Example 15, Step C). MS (ES): 554.2 [M+H]−.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH:24]=[CH:25][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[NH2:32][C@@H:33]([CH2:37][CH2:38][C:39]([NH:41][C@H:42]([C:45]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:46])[CH2:43][SH:44])=[O:40])[C:34]([OH:36])=[O:35]>C(Cl)Cl.CO>[NH2:32][C@@H:33]([CH2:37][CH2:38][C:39]([NH:41][C@@H:42]([CH2:43][S:44][CH2:30][CH2:29][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=3)[N:4]=2)[CH:22]=1)=[O:31])[C:45]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:46])=[O:40])[C:34]([OH:36])=[O:35]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Solvent: ClCCl
Solvent: CO
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)CCSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a suspension of N-(3-{5-fluoro-2-[4-(2-methoxy-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-acrylamide 3 (0.1 g, 0.236 mmol) and glutathione (0.1 g, 0.325 mmol) in DCM (10 mL) and CH3OH (10 mL) was added TEA (0.1 g, 0.988 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 16 h and then concentrated. The residue was washed with H2O and dried to afford the title compound, (S)-2-amino-5-((R)-1-(carboxymethylamino)-3-(3-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenylamino)-3-oxopropylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic acid (0.17 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1nc2c(s1)C(N1CCOCC1)COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.954 mmol) in THF (6 mL) was added morpholine (416 mg, 4.775 mmol). The reaction mixture was stirred at 60° C. for 5 h. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford crude product as yellow oil. The oily product was stirred in n-Hexane (6 mL) at room temperature for 0.5 h and then filtered to afford compound 9-Bromo-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (300 mg, 75%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=2.6 Hz, 1H), 7.48 (dd, J1=8.6 Hz, J2=2.6 Hz, 1H), 7.13 (d, J1=8.64 Hz, 1H), 4.55 (dd, J1=12.08 Hz, J2=3.32 Hz, 1H), 4.40 (dd, J1=6.6 Hz, J2=3.2 Hz, 1H), 4.31 (m, 1H); 3.94 (s, 31-1) 3.56 (m, 4H); 2.68 (m, 4H); LC-MS (ESI & APCI): 427.2 (M+2).
Reaction SMILES: N.[Na].C([N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]=2[CH:12]=[CH:11]1)C1C=CC=CC=1>CCOCC>[CH:20]1([O:19][C:18]2[C:13]3[CH:12]=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: c1ccc(Cn2ccc3c(OC4CCCCC4)ncnc32)cc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: c1nc(OC2CCCCC2)c2cc[nH]c2n1
Temperature: -78 °C
Yield: 9.4 %

Procedure:
To liquid ammonia (6.0 mL) at −78° C. was added 33 mg (1.43 mmol) sodium metal and the resulting dark blue solution stirred at −78° C. 10 min. A solution of 75 mg (0.244 mmol) of the product from Method M in 3.0 mL of ether was added dropwise over a 5 min period. The resulting solution stirred at −78° C. for 1 h followed by quenching upon addition of 500 mg of solid ammonium chloride. After evaporation at room temperature, the residual solid was triturated with 25 mL of ethylacetate containing 1 mL of acetic acid for 1 h. Filtration and concentration in vacuo afforded crude material which was purified by preparative thin layer chromatography (silica-gel; 2:1 ethyl acetate/hexanes) to produce 5 mg of the title compound. 1H NMR (400 MHz) (CDCl3) δ: 1.27-1.35 (m, 6H), 1.62-1.67 (m, 4H), 5.30-5.36 (m, 1H), 6.55 (d, 1H, J=3.2 Hz), 7.11 (d, 1H, J=3.2 Hz), 8.37 (br s 1H). LRMS: 218.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][NH:7][C:8]=1I)([CH3:3])[CH3:2].[CH3:10][C:11]1[CH:12]=[C:13]([SH:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1.[H-].[Na+]>CN(C)C=O>[CH3:10][C:11]1[CH:12]=[C:13]([S:18][C:8]2[NH:7][CH:6]=[N:5][C:4]=2[CH:1]([CH3:3])[CH3:2])[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: CC(C)c1nc[nH]c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2[nH]cnc2C(C)C)c1
Temperature: 140 °C
Yield: 52.8 %

Procedure:
In 30 ml of dry N,N-dimethylformamide was dissolved 4.0 g (16.9 mmol) of 4-isopropyl-5-iodo-1H-imidazole (4b), followed by addition of 4.68 g (33.9 mmol) of 3,5-dimethylthiophenol and 2.1 g (52.5 mmol) of 60% sodium hydride. The mixture was heated at 140° C. for 7 hours. The N,N-dimethylformamide was there distilled off under reduced pressure and, after addition of dry ice, the residue was extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was fractionated by silica gel chromatography (3% methanol-methylene chloride). The eluted crude compound was recrystallized from ethyl acetate-diisopropyl ether to provide 2.2 g (yield 53%) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1H-imidazole (X=Y=Me) (9).
Reaction SMILES: [N:1]1([C:7]2[C:8]([CH2:13][NH2:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][C:16]1[C:17]([CH:23]=O)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:15][C:16]1[C:17]([CH2:23][NH:14][CH2:13][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: NCc1ncccc1N1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cnc(CNCc2ncccc2N2CCCCC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of C-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl)-methylamine, 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-ylmethyl)-amine. 1H NMR (CDCl3) δ 1.50-1.57 (m, 2H), 1.63-1.72 (m, 4H), 2.24 (s, 3H), 2.28 (s, 3H), 2.82 (t, 4H, J=5.1 Hz), 3.91 (s, 2H), 4.01 (s, 2H), 7.07 (dd, 1H, J=4.5, 8.1 Hz), 7.20 (s, 1H), 7.28 (dd, 1H, J=1.2, 8.1 Hz), 8.20 (s, 1H), 8.23 (dd, 1H, J=1.2, 4.5 Hz). Further reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-ylmethyl)-amine, 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde and NaBH(OAc)3 following General Procedure B gave a colorless oil. Deprotection with NH2NH2.H2O following General Procedure E, and subsequent conversion to the HBr salt, gave COMPOUND 202 as a yellow solid. 1H NMR (CD3OD) δ 1.55-1.83 (m, 10H), 2.51 (s, br. 6H), 2.71-2.76 (m, 2H), 2.922 (t, 2H, J=7.5 Hz), 3.00-3.04 (m, 4H), 4.32 (s, 2H), 4.33 (s, 2H), 7.89 (dd, 1H, J=5.7, 8.4 Hz), 8.20 (d, 1H, J=8.4 Hz), 8.23 (s, 1H), 8.56 (d, 1H, J=5.7 Hz), 8.62 (s, 1H); 13C NMR (D2O) δ 17.20, 17.45, 23.08, 23.45, 25.04, 25.73, 39.68, 52.55, 53.42, 54.35, 56.32, 126.47, 133.78, 135.55, 137.45, 137.74, 147.08, 147.50, 148.70, 150.86. ES-MS m/z 382 (M+H). Anal. Calcd. for C23H35N5O.3.8HBr.0.9H2O.0.3C4H10O: C, 39.96; H, 6.04; N, 9.63; Br, 41.74. Found: C, 39.93; H, 6.08; N, 9.64; Br, 41.68.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][CH:5]1[O:11][C:12]([CH:14]1[CH2:18][C:17](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:16][N:15]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:13])([CH3:3])[CH3:2]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][CH:5]1[O:11][C:12]([CH:14]1[CH2:18][CH:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:16][N:15]1[C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[O:13])([CH3:3])[CH3:2]
Reactant: CC1CCC(C(C)C)C(OC(=O)C2CC(=Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)C2CC(Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
4-(3-Fluoro-benzylidene)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl)ester (1.20 g, 2.61 mmol) was dissolved in ethyl acetate:toluene (1:1, 12 ml). The solution was submitted to hydrogenation on platinum oxide (120 mg, 10% by weight) at 25° C. and 15 psi for 1 hour. The reaction mixture was filtered through arbocel and the filtrate reduced under pressure. The residue was purified by flashmaster chromatography eluting with heptane:ethyl actetate (15:1) to yield the title compound as a colourless oil (1.11 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=O)[C:6]=1[CH:16]=[CH2:17])=[O:4].BrBr.NC(N)=[S:22].[OH-].[NH4+]>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[S:22][CH:17]=[CH:16][C:6]=12)=[O:4]
Reactant: NC(N)=S
Reactant: C=Cc1c(C(=O)OC)c2ccccc2[nH]c1=O
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c2ccccc2nc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.8 g (7.2 mmol) Methyl-2-oxo-3-vinyl-1,2-dihydroquinoline-4-carboxylate 5 in 40 mL chloroform was added slowly over a dropping funnel a solution of 1.15 g (7.2 mmol) bromine in 40 mL chloroform and the reaction mixture was stirred for 1 hour at ambient temperature. After evaporation of the solvent the residue was mixed with 40 mL ethanol and 1.7 g (18 mmol) thiourea and refluxed for 2.5 h. After cooling the mixture was poured on ice, the pH-value was adjusted with ammonium hydroxide at pH=7-8 and the solution was extracted with 100 mL chloroform. The organic layer was separated, dried over sodium sulfate and filtered. Then the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with methylene chloride/acetone 9:1, to give 1.0 of the desired product 14.