Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[N-:48]=[N+:49]=[N-:50].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]2[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:50]=[N:49][N:48]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: Cc1cc(CC(NC(=O)OCc2ccccc2)C(=O)NCC(C)(C)C)cc2cn[nH]c12
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC(NC(=O)OCc2ccccc2)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl 3-(7-methyl-1H-indazol-5-yl)-1-(neopentylamino)-1-oxopropan-2-ylcarbamate (0.17 g, 0.402 mmol) in chloroform (0.5 mL) was added to a mixture of phosphorus pentachloride (0.17 g, 0.802 mmol) and quinoline (0.2 mL) in chloroform (1.0 mL). After stirring at room temperature for 2 h, the solvents were removed in vacuo. The crude mixture was dissolved in acetonitrile (2.0 mL) and treated with sodium azide (78 mg, 3.0 equiv). After stirring the mixture at 40° C. overnight, the solvents were removed and the crude mixture dissolved in methylene chloride which was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded 73 mg (40%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 0.82 (s, 9H), 2.46 (s, 3H), 2.30-3.46 (m, 2H), 3.69 (d, J=14.3, 1H), 3.93 (d, J=14.3, 1H), 4.98-5.13 (m, 2H), 5.30 (m, 1H), 6.02 (d, J=8.9, 1H), 6.86 (s, 1H), 7.25-7.35 (m, 5H), 7.94 (s, 1H). Mass spec.: 448.19 (MH)+.
Reaction SMILES: C[O-].[Na+:3].[CH2:4]([O:6][N:7]=[C:8]([C:11]1[C:12](=[O:28])[CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH2:15][C:16]=1[OH:17])[CH2:9][CH3:10])[CH3:5]>CO>[CH2:4]([O:6][N:7]=[C:8]([C:11]1[C:16](=[O:17])[CH2:15][CH:14]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=2)[CH2:13][C:12]=1[O-:28])[CH2:9][CH3:10])[CH3:5].[Na+:3]
Reactant: CCON=C(CC)C1=C(O)CC(c2ccc(C(=O)OC)cc2)CC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCON=C(CC)C1=C([O-])CC(c2ccc(C(=O)OC)cc2)CC1=O

Procedure:
Into 10.8 g of methanol containing 2.5% of sodium methoxide was dissolved 1.7 g of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(4-methoxycarbonylphenyl)-2-cyclohexen-1-one and the solvent was removed from it under reduced pressure. Thus, 1.8 g of colorless desired crystals were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=[O:15])[CH2:7][CH2:6]2.[CH:16](I)([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Reactant: CC(C)I
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)C(C(C)C)C(=O)CC2
Reaction time: 0.5 h

Procedure:
22.0 g of 3,4-dihydro-6,7-dimethoxy-2(1H)-naphthalenone were dissolved in 300 ml of dimethylformamide and treated with 13 g of potassium tert.-butylate. The solution was stirred at 18° for 30 minutes. After the addition of 19.7 g of isopropyl iodide the mixture was stirred for a further 30 minutes, whereby the temperature was held below 30°, and then poured into water. The product was extracted with ether, the extract was washed with water, dried over magnesium sulfate and evaporated. The oil which remained behind was purified by column chromatography (silica gel, hexane/ethyl acetate 6:1). There was obtained 3,4-dihydro-6,7-dimethoxy-1-isopropyl-2(1H)-naphthalenone, m.p. 77°-79°.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-])=[O:29])=[C:11]2[CH3:31])N=1.CCN(C(C)C)C(C)C.[NH2:41][C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]1[OH:48]>CN(C=O)C>[OH:48][C@H:43]1[CH2:44][CH2:45][CH2:46][CH2:47][C@@H:42]1[NH:41][C:28]([C:12]1[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]2\[C:17](=[O:26])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[NH:10][C:11]=1[CH3:31])=[O:29]
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To the solution of A4 (100 mg, 0.24 mmol) and DIEA (140 mg, 0.96 mmol) in 10 mL of DMF, was added (1S,2S)-2-Amino-cyclohexanol (45 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol), dried under vacuum to provide to provide title compound (70 mg, 74% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.62 (s, 1H), 10.88 (s, 1H), 7.71-7.77 (m, 2H), 7.36-7.39 (d, 1H), 6.81-6.95 (m, 2H), 4.58-4.60 (d, 1H), 3.48-3.60 (m, 1H), 3.30-3.35 (m, 1H), 2.41-2.44 (ds, 6H), 1.88-1.90 (t, 2H), 1.62 (S, 2 h), 1.23 (s, 4H). LC/MS: 398.1 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([Cl:15])[C:9]=2[S:8][CH:7]=1)(=O)C.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:15][C:14]1[C:9]2[S:8][CH:7]=[C:6]([CH2:5][OH:4])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CC(=O)OCc1csc2c(Cl)ncnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1csc2c(Cl)ncnc12
Reaction time: 0.5 h

Procedure:
(4-Chlorothieno[3,2-d]pyrimidine-7-yl)methyl acetate (3.12 g, 12.06 mmol) was dissolved in THF (240 mL) and then 1N NaOH solution (100 mL) was added thereto at room temperature. The reaction mixture was stirred for 30 minutes, diluted with ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated to obtain the title compound as a white solid without further purification.
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[Cl:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[C:14]2([CH3:22])[CH3:21])[C:10]([F:23])=[C:9]([NH:24][NH2:25])[N:8]=1.[CH:26]1([CH2:31][C@H:32]([CH2:36][N:37]([CH:46]=[O:47])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:33](O)=[O:34])[CH2:30][CH2:29][CH2:28][CH2:27]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[Cl:6][C:7]1[N:8]=[C:9]([NH:24][NH:25][C:33](=[O:34])[C@H:32]([CH2:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:36][N:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:46]=[O:47])[C:10]([F:23])=[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[C:14]2([CH3:21])[CH3:22])[N:12]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CN(C)C1CCN(c2nc(Cl)nc(NN)c2F)C1(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CN(C)C1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)C1(C)C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of racemic 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,2,2-tetramethyl-3-pyrrolidinamine pentahydrochloride (0.3649 g, 0.752 mmol) in DMF (5 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.2140 g, 0.701 mmol), N-methylmorpholine (0.770 mL, 7.00 mmol), 1-hydroxy-7-azabenzotriazole (114 mg, 0.838 mmol), and EDC (161 mg, 0.840 mmol). The solution was stirred overnight and purified directly by Gilson RPLC to provide [(2R)-3-(2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1755 g, 42% yield, mixture of diastereomers) as a brown oil. LCMS: (M+H)+: 590.4.
Reaction SMILES: [CH3:1][N:2](C)[C:3](Cl)=O.[CH2:7]([NH:15][C:16](=O)[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C.[OH-].[Na+].C(=O)([O-])[O-].[Ca+2]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:3])[C:16](=[N:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:17]
Reactant: CCCCCCCCNC(C)=O
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCN=C(C)N(C)C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
Dimethylcarbamyl chloride (6.86 g, 63.7 mmol) was added slowly to 10.0 g (63.7 mmol) of N-octyl acetamide in 10 mL of dry toluene and the solution was refluxed under a nitrogen atmosphere for 16 h. The volatile materials were removed on a rotary evaporator in vacuo. The residue, dissolved 30 mL of dichloromethane, was stirred vigorously with a solution of 2.55 g (63.7 mmol) of sodium hydroxide in 40 mL of water for 30 min. Calcium carbonate (2.55 g) was added to the mixture and stirring was continued for an additional 30 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 mL×3). The combined organic phases were dried (calcium carbonate) and the solvent was removed on a rotary evaporator. The residue was distilled at 63-64° C./0.25 Torr to yield 6.2 g (53%) of product (purity 99% by GC). IR 2956, 2925, 2854 (C—H), 1626 (N═C) cm−1. 1H NMR 3.17 (t, 2H, JHH 7.5 Hz, —CH2—N═), 2.86 (s, 6H, —N—(CH3)2); 1.87 (s, 3H, —N═C(CH3)—N); 1.5 (m, 2H, —CH2—CH2—N═); 1.25-1.4 (m, 10H, CH3—(CH2)5—); 0.88 (t, 3H, JHH 7.2 Hz, CH3).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Br:12])[CH:5]=1)(=[O:3])[CH3:2].C(Cl)(Cl)[Cl:14]>>[NH2:11][C:7]1[C:8]([Cl:10])=[N:9][C:4]([C:1](=[O:3])[CH2:2][Cl:14])=[CH:5][C:6]=1[Br:12]
Reactant: CC(=O)c1cc(Br)c(N)c(Cl)n1
Reactant: ClC(Cl)Cl
Product: Nc1c(Br)cc(C(=O)CCl)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.8 g (3.2 mmol) of 6-acetyl-3-amino-4-bromo-2-chloro-pyridine are dissolved in 5 ml of CHCl3, and 462 mg (3.42 mmol) of SO2Cl2, dissolved in 5 ml of CHCl3, are added. The mixture is stirred at room temperature for 30 minutes and then poured onto NaHCO3 solution and extracted with CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)CCCCCCCn1ccnc1)c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(NCCCCCCCCn1ccnc1)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52d, a solution of N-[1-(4-chlorophenyl)-1-methylethyl]-8-(imidazol-1-yl)octanamide (5.9 g) in THF (130 ml) was reduced with BH3/THF (64.5 ml of a 1M solution) to give N-[1-(4-chlorophenyl)-1-methylethyl]-8-(imidazol-1-yl)octylamine, b.p. 210° C. (0.05 mmHg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 20 °C
Yield: 89.1 %

Procedure:
2-(3-Chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (28.1 g), triethylamine (14 cc) and 1-(4-fluorophenyl)piperazine (18.8 g) in toluene (300 cc) are heated for 8 hours at boiling point. The mixture is then cooled to a temperature of about 20° C. and stirring is maintained for 15 hours at this temperature. The precipitate formed is separated by filtration and washed with toluene (2 x 50 cc). The filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.1-1.5 bar) with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (150 cc). 2-{3-[4-(4-Fluorophenyl)-1piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (37.8 g) is obtained, m.p. 95°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:11])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-chlorobenzyl alcohol (14.26 g, 100 mmol) in CH2Cl2 (40 mL) at ambient temperature was added added dropwise a solution of PBr3 in CH2Cl2 (1.0M, 32 mL, 32 mmol). The reaction mixture was stirred for 72 hours at ambient temperature and then was poured slowly onto ice. The layers were separated and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 4-chlorobenzyl bromide (19.76 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)c(C#N)c(NCCO)n1
Reactant: NCc1cccnc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO

Procedure:
In analogy to the procedure described in example 47a, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-methanesulfonyl-pyrimidine-5-carbonitrile was treated with 3-picolyl-amine in dioxane in the presence of N-ethyl-diisopropylamine at 40° C. to yield 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as a brown solid which was used in the next step without further purification and characterization.
Reaction SMILES: N1CCCCC1.C1(NC(N2C3C(=CC(OC4C=CN=C(N(C(OC5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)C=4)=CC=3)C=C2)=O)CC1.[CH:48]1([NH:51][C:52]([N:54]2[C:62]3[C:57](=[CH:58][C:59]([O:63][C:64]4[CH:69]=[CH:68][N:67]=[C:66]([NH:70][C:71]([N:73]5[CH2:78][CH2:77][CH:76](N6CCCC6)[CH2:75][CH2:74]5)=[O:72])[CH:65]=4)=[CH:60][CH:61]=3)[CH:56]=[CH:55]2)=[O:53])[CH2:50][CH2:49]1>CN(C)C=O>[CH:48]1([NH:51][C:52]([N:54]2[C:62]3[C:57](=[CH:58][C:59]([O:63][C:64]4[CH:69]=[CH:68][N:67]=[C:66]([NH:70][C:71]([N:73]5[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]5)=[O:72])[CH:65]=4)=[CH:60][CH:61]=3)[CH:56]=[CH:55]2)=[O:53])[CH2:50][CH2:49]1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Agent: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCCCC1
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and piperidine (0.42 ml, 4.2 mmol) were added to a mixture (467 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate obtained in Example 68; and the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; the obtained solid was washed with a solvent mixture of hexane: diethyl ether 1:1 to yield the title compound as crystals (241 mg, 0.57 mmol).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 90 °C

Procedure:
4-Bromo-3-chloroaniline (2.0 g, 9.7 mmol), (4-chlorophenyl)boronic acid (2.0 g, 12.7 mmol), Pd(dppf)Cl2 (713 mg, 1.0 mmol), 2M aqueous Na2CO3 (12.2 mL, 24.4 mmol) were dissolved in 1,4-dioxane (30 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature, then diluted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), concentrated and diethyl ether was added. The resulting precipitate was filtered and dried in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][C@H:9]([O:11]CC2C=CC=CC=2)[CH2:8][C@H:7]1[CH2:19][CH2:20][O:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[CH2:19][CH2:20][O:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCOc1c(C)cccc1CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1c(C)cccc1CCc1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
2260 mg of (2R,4R)-1-ethoxycarbonyl-4-benzyloxy-2-{2-[6-methyl-2-(2-phenylethyl)phenoxy]ethyl}pyrrolidine [prepared as described in step (a) above] were dissolved in 20 ml of ethanol, and then 300 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The resulting mixture was stirred under a hydrogen atmosphere at atmospheric pressure and at 60° C. for 1.5 hours. At the end of this time, the catalyst was removed by filtration, and the reaction mixture was concentrated by evaporation under reduced pressure. The resulting concentrate was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 1840 mg (a quantitative yield) of the title compound as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][C:20]([CH3:35])([CH3:34])[CH2:21][CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C@@H:10]([OH:18])[CH2:11][CH:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:37]1(C)[CH:42]=CC(S(O)(=O)=O)=C[CH:38]=1.COC(OC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:19][C:20]([CH3:34])([CH3:35])[CH2:21][CH2:22][O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])[C@H:10]([CH2:11][CH:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH2:14])[O:18][C:37]1([CH3:42])[CH3:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(C[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: C=CC(C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)C(C)C

Procedure:
4.4 g of 6(S)-tert-butoxycarbonylamino-8,8-dimethyl-5(S)-hydroxy-3(R,S)-isopropyl-10-triisopropylsilyloxydec-1-ene and 134 mg of p-toluenesulfonic acid hydrate are stirred in 25 ml of methylene chloride and dimethoxypropane at room temperature for 2 h. After the reaction mixture has been concentrated, the residue is purified over 500 g of silica gel by means of FC (mobile phase D): Rf (D)=0.61.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:23][NH2:24])=[CH:25][CH:26]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2CCN(c3ccc(C#N)cc3)CC2)c(C)c2c1OC(C)(C)C2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(C)c(N2CCN(c3ccc(CN)cc3)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To the THF (5.0 mL) solution of 4-[4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]benzonitrile (180 mg, 0.479 mmol) synthesized in Example 90, lithium aluminum hydride (91 mg, 2.39 mmol) was slowly added under ice cooling, followed by stirring for 1.5 hours. To the reaction solution, sodium sulfate.10 hydrate (500 mg) was added. The temperature was raised to room temperature and the mixture was stirred for 16 hours. Undissolved residues were removed by filtration and the filtrate was concentrated under reduced pressure. To the resulting residue, hexane was added. The resulting solids were filtered to obtain the title compound 120 mg (yield 66%). Melting point was 156 to 158° C. (hexane-THF).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([NH:38]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:39]=[CH:40][CH:41]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(Cc2cccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)c2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-(4-methylpiperazinomethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13]#[N:14].F[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:13]#[N:14])=[C:2]([NH:1][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[S:6][C:5]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COc1ccc2c(C#N)c(N)sc2c1
Product: COc1ccc2c(C#N)c(Nc3cc(F)ccc3[N+](=O)[O-])sc2c1
Yield: 29 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-6-methoxybenzo[b]thiophene-3-carbonitrile (5.2 g) and 2,4-difluoro-nitrobenzene (4.0 g), 6-methoxy-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (2.5 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=O.[F:22][C:23]([F:31])([F:30])[C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27]>C(O)(=O)C.S(=O)(=O)(O)O>[F:22][C:23]([F:31])([F:30])[C:24]([C:25]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:27])=[O:29]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
To a stirred solution of 50 mg (0.15 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methanesulfonyl-phenyl)-methanone in 2 ml acetic acid was added 0.020 ml (0.15 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 20 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 18 mg (27%) 2,2,2-trifluoro-1-[4-(4-methanesulfonyl-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light brown solid. ES-MS m/e (%): 440 (M+H+, 100).