Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](O)=[O:47])[C:41]2=[O:49])=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:19]2[CH2:20][C:21]3[C:12]([O:11][C:7]4[CH:6]=[C:5]5[C:10]([C:2]([NH:1][C:46]([C:42]6[C:41](=[O:49])[N:40]([C:37]7[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=7)[CH:45]=[CH:44][CH:43]=6)=[O:47])=[N:3][N:4]5[CH3:32])=[CH:9][CH:8]=4)=[CH:13][CH:14]=[N:15][C:16]=3[NH:17][C:18]2=[O:31])=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc5c(NC(=O)c6cccn(-c7ccc(F)cc7)c6=O)nn(C)c5c4)ccnc3NC2=O)cc1
Yield: 18.9 %

Procedure:
A solution of compound 276 (100.00 mg; 0.23 mmol; 1.00 eq.), 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (59.59 mg; 0.26 mmol; 1.10 eq.), pybop (157.16 mg; 0.30 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (115.48 μl; 0.70 mmol; 3.00 eq.) was stirred at room temperature for 22 hours. The reaction was concentrated, redissolved in DMSO and purified via prep HPLC to afford 28 mg (16%) of 278 as an off-white solid. LC-MS (M+H=646, obsd.=646).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:27][O:26][CH2:25][CH2:24][O:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1
Reactant: COCCOc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COCCOc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-(2-methoxyethoxy)phenyl)-5-phenylbenzoxazole (171 mg, 0.47 mmol) and 1,2,4-benzenetricarboxylic anhydride (90 mg, 0.47 mmol) the title compound was obtained (141 mg, 56%). 1H NMR (DMSO) δ 8.57(dd, 1H), 8.46(s, 1H), 8.34(d, 1H), 8.24(d, 1H), 8.19(d, 1H), 7.97(d, 1H), 7.85(m, 4H), 7.63(t, 3H), 7.53(t, 1H), 4.51(t, 2H), 3.95(t, 2H), 3.52(s, 3H). MS 535 m/z (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 44.9 %

Procedure:
Ethyl 2-aminobenzo[b]thiophene-3-carboxylate (69.3 g) and 2,4-difluoronitrobenzene (50 g) were dissolved in dimethyl sulfoxide (550 Ml) and heated to 50° C. Thereto was added potassium carbonate (63 g) and the mixture was stirred at 100° C. for 70 min. After cooling, the reaction mixture was allowed to cool to 70° C. and poured into water (2.5 L). The reaction mixture was allowed to stand still, and filtered. The filtrated orange crystals were washed with ethyl acetate to give ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (50.7 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH:21]1[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[N:18][N:19]=[N:20]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C1CC(c2nnn[nH]2)CCN1
Yield: 94.2 %

Procedure:
A mixture of 4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester (0.6 g, 2.08 mmol) and activated 10 wt. % palladium on carbon (0.065 g) in ethanol (35 mL) was stirred vigorously under 1 atmosphere hydrogen atmosphere for 4 hours. The reaction mixture was then filtered through a microglass filter paper and the solid washed abundantly with methanol and water. The solvent was evaporated in vacuo to yield the 4-(1H-tetrazol-5-yl)-piperidine as a white solid (0.30 g, 94%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N+](=[CH2:15])=[N-]>O1CCCC1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
Under ice-cooling, to a solution of 910 mg of 1H-5-indazolecarboxylic acid in 60 ml tetrahydrofuran was added an excess amount of a solution of diazomethane in diethyl ether, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, the residue was added with 50 ml of ethyl acetate, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 923 mg of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][C:8](=[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 72.9 %

Procedure:
A mixture of 900 mg (2.06 mmole) of 4-(diphenylmethylene)-1-(3-phthalimidopropyl)piperidine (prepared as described in Preparation 10'), 350 mg (7 mmole) of hydrazine hydrate and 20 ml of ethanol was heated under reflux for 2 hours. At the end of this time, the crystals which precipitated were filtered off and the solvent was removed from the filtrate by distillation under reduced pressure, to afford 460 mg (yield 73%) of the title compound as an oil.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[O:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:28]1[C:32]2([CH2:37][CH2:36][N:35]([C@H:2]3[CH2:19][C@@:18]4([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]5[C@@H:17]4[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@H:9]5[CH2:10][C@H:11]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[C@@H:12]4[OH:21])[CH2:4][C@@H:3]3[OH:1])[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Reactant: C1CC2(CCN1)OCCO2
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Yield: 79.88 %

Procedure:
2α,3α-Epoxy-16β-(1-piperidinyl)-5α-androstane-17β-ol is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to give the title compound in a yield of 79.88%, m.p.: 216°-218° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CCCC5)sc34)cc2n1C

Procedure:
This material was prepared from the reaction of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.44 (1H, d, J=5.5 Hz), 7.85 (1H, s), 7.83 (1H, d, J=10.0 Hz), z 7.35 (1H, d, J=1.9 Hz), 7.01 (1H, dd, J=1.9, 8.5 Hz), 6.66 (1H, d, J=5.5 Hz), 3.88 (2H, m), 3.67 (7H, m), 3.54 (2H, m), 2.63 (3H, s), 1.83–2.10 (6H, m). LCMS (ESI+) [M+H]/z Calc'd 493. found 493.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([C:41]3[CH:42]=[N:43][N:44]([CH2:46][C:47]#[N:48])[CH:45]=3)=[C:35]2[CH:34]=[N:33]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ICC>C1COCC1>[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([C:41]3[CH:42]=[N:43][N:44]([CH:46]([CH2:1][CH3:2])[C:47]#[N:48])[CH:45]=3)=[C:35]2[CH:34]=[N:33]1
Reactant: CC(C)NC(C)C
Reactant: N#CCn1cc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C#N)n1cc(-c2ccnc3[nH]ncc23)cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
A solution of diisopropylamine (229.8 mg, 318.3 μL, 2.271 mmol) in THF (10 mL) at 0° C. was treated with butyllithium (698.8 μL of 2.5 M, 1.747 mmol) and then allowed to cool to −78° C. This was then added dropwise to a solution of 2-[4-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)pyrazol-1-yl]acetonitrile (815 mg, 1.747 mmol) over a period of 20 minutes. After a further 30 minutes the reaction was treated with iodoethane (544.9 mg, 279.4 μL, 3.494 mmol) at −78° C. and the ice bath removed. The reaction was allowed to stir for 1.5 hours and then treated with brine/EtOAc and the two layers separated. The organics were dried (MgSO4), filtered and concentrated. The resultant residue was taken up in DCM (12 mL) and treated with triethylsilane (4 mL) and TFA (0.5 mL) and allowed to stir at RT for 2 hours. The reaction was concentrated in vacuo and purified by column chromatography (10% MeOH/DCM) to give the product as a pure white solid (252 mg, 57% Yield). 1H NMR (DMSO, 400 MHz) δ 0.95 (3H, t), 2.23-2.28 (2H, m), 5.79 (1H, t), 7.46 (1H, d), 8.46 (1H, s), 8.48 (1H, d), 8.52 (1H, d), 8.83 (1H, s), 13.73 (1H, br s); MS (ES+) 253.09
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl.Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([C:31]5[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=5)[CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:11])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCN(c2ccncc2)CC1
Yield: 28.5 %

Procedure:
(Method B) A mixture of 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone (471 mg), 4-chloropyridine hydrochloride (225 mg) and triethylamine (405 mg) in ethanol (20 ml) was reacted in a sealed tube at 150° C. for 18 hours. The reaction mixture was concentrated, and the residue was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with dichloromethane. The extract was washed with water and brine, dried and concentrated to obtain a residue, which was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=12:1) and crystallized from a mixture of ethanol and diethyl ether to obtain the title compound (156 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:29]1[C:30]([OH:38])=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:23]([C:29]1[C:30]([OH:38])=[C:31]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:32]=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: CCCCCCc1cccc(B(O)O)c1O
Product: CCCCCCc1cccc(-c2cccc(-c3cccc(-c4cc(OC)ccc4O)n3)n2)c1O
Yield: 57 %

Procedure:
6-(3-Hexyl-2-hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 3-hexyl-2-hydroxyphenylboronic acid in 57% yield using method F; δH [2H6]-DMSO 12.40,(1H, s), 8.36,(2H, m), 8.25,(2H, t), 8.18,(1H, d), 8.09,(1H, d), 7.96,(1H, d), 7.65,(1H, s), 7.25,(1H, d), 6.99,(1H, d), 6.96-6.8,(2H, m), 3.81,(3H, s), 2.67,(2H, t), 1.60,(2H, m), 1.42-1.25,(6H, m), 0.88,(3H, t); MS 455 (MH)+; HPLC retention time (system 1) 4.96 minutes.
Reaction SMILES: [CH3:1][C@@H:2]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:3]([NH:8]C(OCC1C=CC=CC=1)=O)[C:4]([O:6][CH3:7])=[O:5]>C(O)(=O)C.[C].[Pd]>[NH2:8][C@H:3]([C:4]([O:6][CH3:7])=[O:5])[C@@H:2]([CH3:1])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C
Yield: 96.4 %

Procedure:
12.92 Grams (40 mmols) of Z-Thr-(tBu)-OMe in 200 ml of glacial acetic acid and 3 g of palladium carbon (10% Pd) are hydrogenated at room temperature. The absorption of hydrogen ceases after one hour. The catalyst is filtered off and the filtrate evaporated at 35° C. in a water-jet vacuum. The residue is dried in a high vacuum at 35° C. and yields 7.3 g of an oil which is unitary according to its thin-layer chromatogram and can be further used as it is.
Reaction SMILES: CI.[NH2:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=S>C(O)C>[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:4]2[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[N:3]2
Reactant: Cc1cccc(N)c1CNC(=S)Nc1cccc(C(F)(F)F)c1
Solvent: CI
Solvent: CCO
Product: Cc1cccc2c1CNC(Nc1cccc(C(F)(F)F)c1)=N2
Yield: 8.9 %

Procedure:
A mixture of methyl iodide (167 mg, 1.18 mmol) and 1-(2-amino-6-methyl-benzyl)-3-(3-trifluoromethyl-phenyl)-thiourea (50 mg, 0.147 mmol) in ethanol (3 ml) was heated to reflux for 3 h. The solvent was evaporated under reduced pressure, the residue was taken up in ethyl acetate, washed (water), and dried (Na2SO4). After evaporation of the solvent under reduced pressure, the title compound (4 mg, 8.9%, MS: m/e=306.1 [M+H+]) was obtained by HPLC purification of the residue (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])[N:7]=[C:6]1[C:25]([OH:27])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.O.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][NH2:48])[CH:42]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=2)=[O:12])[N:7]=[C:6]1[C:25]([NH:48][CH2:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1)=[O:27]
Reactant: NCc1cccnc1
Reactant: COCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
38.8 mg (0.1 mmol) of 1-(2-methoxyethyl)-4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1H-imidazole-2-carboxylic acid (Example 9A) are dissolved in 0.4 ml of DMF and, after addition of 81 mg (0.5 mmol) of N,N-carbonyldiimidazole, stirred at room temperature for 50 minutes. Then 18 μl (18 mg; 1 mmol) of water are added, and the mixture is stirred at room temperature for 30 minutes. Addition of 21.6 mg (0.2 mmol) of 3-picolylamine is followed by stirring at room temperature for 90 minutes. After filtration, the reaction mixture is purified by preparative HPLC (column: Macherey-Nagel VP 50/21 Nucleodur C18 gravity, 5 μm; flow rate: 25 ml/min; eluent A: acetonitrile, eluent B: water+0.1% conc. aqueous ammonia solution, gradient: 0 min 10% A, 2.00 min 10% A, 6.00 min 90% A, 7.00 min 90% A, 7.10 min 10% A, 8 min 10% A; running time: ca. 10 min per separation; wave length: 220 nm). The correct fractions are evaporated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C([N-]C(C)C)(C)C.[Li+].[Br:19]C(Cl)(Cl)C(Cl)(Cl)Br.O>C1COCC1>[Br:19][C:10]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncc(Br)c1Br
Temperature: -55 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
A cooled (−70° C.) solution of 5-bromonicotinic acid (12.6 g, 62.5 mmol) in THF under nitrogen was treated with 2 M lithium diisopropylamide (72 mL, 144 mmol) dropwise over 1 h. The solution stirred for 2.5 h at −55° C. The mixture was then cooled to −70° C. and treated with 1,2-dibromotetrachloroethane (25 g, 77.2 mmol) in portions over 30 min. After 1 h, the reaction mixture was allowed to warm to −20° C. over 2 h and then water (75 mL) was added slowly. The organic layer was then evaporated in vacuo and the aqueous residue was diluted with water (250 mL), then washed with ethyl acetate. The aqueous layer was then acidified to pH 3 by addition of concentrated hydrochloric acid. The precipitated solid was collected by filtration and dried at 60° C. in vacuo to afford 10 g (57%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.75 (s, 1H), 3.2 (br. s, 1H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:8]([CH3:20])=[C:9]([C:13](OC(C)(C)C)=[O:14])[NH:10][C:11]=1[CH3:12])(=O)C.C(OC(OCC)OCC)C>C(O)(C(F)(F)F)=O>[CH3:20][C:8]1[C:7]([CH2:6][CH2:5][OH:4])=[C:11]([CH3:12])[NH:10][C:9]=1[CH:13]=[O:14]
Reactant: CC(=O)OCCc1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: Cc1[nH]c(C=O)c(C)c1CCO
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
tert-Butyl 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxylate (15 g, 53 mmol) was dissolved in TFA (40 ml) and the solution was stirred at 40° C. under nitrogen for 10 min. The reaction mixture was then cooled to 0° C. and triethylorthoformate (9.6 ml, 58 mmol) was added dropwise. The mixture was allowed to warm up to 20° C. and was stirred for 1 hr before being poured into ice water. This was extracted with dichloromethane and the extracts were washed successively with 10% aqueous ammonia and water and dried over MgSO4. 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxaldehyde was purified by silica gel chromatography using (7:3) ethyl acetate:hexane. Yield 45%, m.p. 125–27° C. (water).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:28]3[CH2:27][CH2:26][C:25](=[C:24]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[CH2:30][CH2:29]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)C1
Yield: 46.9 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.6 g of 4-(bis(4-fluorophenyl)-methylene)piperidine to give 0.5 g of 6-acetyl-3-(2-(4-(bis(4-fluorophenyl)methylene)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 209°-211° C. as axalate thereof.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=2)=[CH:15][CH:16]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1ccccc1F
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3ccccc3F)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[CH2:27]([O:26][C:24](=[O:25])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A biphasic mixture of 2-(4-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in example 1Ga step B, and ethyl chloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) was prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction was then diluted with H2O and extracted with EtOAc (2×). The organic phases were washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 20-40%) gave 48 mg (55%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Under a nitrogen stream, 4-bromo-2-fluorophenol (14.9 g, 78 mmol) and potassium carbonate (13.0 g, 94 mmol) were dissolved in N,N-dimethylformamide (100 mL), followed by addition of benzyl bromide (10.2 mL, 86 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the solvent was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate/hexane:0/100-5/95) to give the title compound (21.9 g, 100%).