Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH3+:14])[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC[C@H]([NH3+])c1cccc(C(C)C)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: [Cl-]
Product: CC[C@H](NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1)c1cccc(C(C)C)c1

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(3-isopropylphenyl)propan-1-aminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 558 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.[CH:41](=O)[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH2:41]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:23][CH2:22]1)[CH3:42]
Reactant: CC=O
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 43.4 mg, 0.0776 mmol), acetaldehyde (17.1 mg, 0.388 mmol), NaBH(OAc)3 (82 mg, 0.388 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford crude product. The crude product was further purified with preparative HPLC to afford product (1.3 mg, 2.14%). LRMS (APCI neg): >97% purity, 254 nm, m/e 587 (M). 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H), 8.36 (d, 1H), 8.31 (d, 1H), 8.03 (dd, 1H), 7.67 (m, 2H), 7.49 (m, 1H), 7.39 (t, 1H), 7.29 (m, 3H), 6.62 (d, 1H), 2.60 (q, 2H), 2.32 (m, 2H), 2.19 (m, 2H), 1.94 (m, 1H), 1.18 (t, 3H), 0.90 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19](OCC)=[O:20])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2].CO.[BH4-].[Li+]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][CH2:19][OH:20])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OCC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
To an ice-cooled and stirred solution of ethyl [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (110 mg) in tetrahydrofuran (8 mL)-methanol (2 mL) was added lithium borohydride (25 mg), and the mixture was stirred at room temperature for 4 h, followed by an addition of lithium borohydride (25 mg). After stirring at room temperature for 3 h, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate:hexane=50:50 to 100:0, volume ratio) to give a colorless oil, which was crystallized from ethyl acetate-hexane to give the title compound (54 mg, 54%) as colorless crystals. MS 462 (MH+). mp 147-148° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(O)(=O)/C=C/C(O)=O.[NH2:23][CH2:24][CH2:25][C:26]#[N:27].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:27][CH2:26][CH2:25][C:24]#[N:23])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N#CCCN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCCC#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 200.3 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (4.95 g, 24.8 mmol) in DMF (25 ml) was added 3-aminopropionitrile fumarate (3.18 g, 12.4 mmol) and DIPEA (15 ml, 84.3 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum and the residue diluted with water (50 mL). It was extracted with EtOAc (3×100 mL) and the organic phase washed with brine solution and dried (Na2SO4). Removal of solvent gave 4-(2-cyanoethylamino)-3-nitro-benzoic acid methyl ester (6.19 g, 98.5%). MS-ESI m/z 250 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.8 (t, 2H), 3.8 (m, 2H), 6.9 (d, 1H), 8.2 (m, 1H), 8.5 (t, 1H), 8.9 (s, 1H)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)O[C:5](=O)[C:4]=1[C:17]([O:19][CH3:20])=[O:18].[C:21]1([N:27]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32]C3=O)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][N:27]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:28]=4)[C:5]=3[C:4]([C:17]([O:19][CH3:20])=[O:18])=[C:3]([S:2][CH3:1])[CH:8]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2ccc(F)cc2)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(F)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 7 h
Yield: 52 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-(4-fluorophenyl)-2H-pyran-3-carboxylate (294 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 7 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 52% of methyl 6-(4-fluorophenyl)-8-(methylthio)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate. White solid; mp-182-184° C.; 1H NMR (300 MHz, CDCl3) δ 2.48 (s, 3H, CH3), 2.82-2.90 (m, 4H, 2CH2), 4.01 (s, 3H, OCH3), 7.10-7.19 (m, 3H, ArH), 7.27-7.36 (m, 3H, ArH), 7.42-7.51 (m, 2H, ArH), 7.67 (d, J=7.62 Hz, 2H, ArH), 7.98 (s, 1H, ArH); MS (ESI) m/z 445 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[O:18])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Product: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylic acid (Z34b) and 4-piperidin-1-ylmethyl-phenylamine. The crude product was purified by column chromatography (silica gel, dichloromethane/EtOH/conc. aqueous ammonia 50:10:0.1).
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Br:5][C:6]1[C:7]([F:13])=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:2][O:3][CH3:4])[C:7]=1[F:13]
Reactant: Oc1cccc(Br)c1F
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chloro(methoxy)methane (11.8 mL) was added at 0 C to a THF (150 mL) solution of 3-bromo-2-fluorophenol (15.0 g) and N,N-diisopropylethylamine (41.1 mL). The reaction mixture was stirred overnight at room temperature in a nitrogen atmosphere and then filtered through celite. The obtained filtrate was washed with 1 M hydrochloric acid and a saturated aqueous solution of sodium bicarbonate in this order, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column (NH, hexane/ethyl acetate), and the solvent was distilled off under reduced pressure to obtain the title compound (17.9 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2([CH2:18][OH:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH:7]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccccc2C1(CO)c1cc(Br)ccc1O
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1Nc2ccccc2C12COc1ccc(Br)cc12

Procedure:
Following the procedure as described in Example 1, and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (25%) as a white solid: mp 225-228° C.; 1H NMR (300 MHz, CDCl3) δ 10.65 (s, 1H), 7.35 (dd, 1H), 7.24 (dt, 1H), 7.11 (d, 1H), 6.99-6.88 (m, 3H), 6.83 (d, 1H), 4.81 (d, 1H), 4.69 (d, 1H); MS (ES+) m/z 316.1 (M+1), 318.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 49.3 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (355 mg, 0.998 mmol) and morpholine (1.3 ml, 15 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (200 mg, 49%), MS (ISP) m/e=407.3 [(M+H)+].
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:13](Br)[CH:14]=[CH2:15]>C(OCC)C>[CH2:15]([O:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: CCOP(=O)(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CCOCP(=O)(OCC)OCC
Temperature: 20 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a hexane washed suspension of 60% sodium hydride (262mg, 6.5 mmol) in diethyl ether (10 ml) was added diethyl hydroxymethylphosphonate (lg, 5.95 mmol) and the reaction mixture stirred for 1 hour at 20° C. under nitrogen. Allyl bromide (0.94 g, 0.67 ml, 7.7 mmol) was then added dropwise and the reaction mixture stirred for 2 hours at 20° C. The solids were filtered off and the filtrate diluted with dichloromethane (30 ml). The solution was washed with water (2×30 ml), dried (MgSO4) and the solvent evaporated to give diethyl allyloxymethylphosphonate (0.85 g, 69%) as a clear liquid needing no further purification. νmax (film) 1260, 1030 and 960 cm-1 ; δH (CDCl3) 1.34(6H, t, J7.3 Hz, 2×CH3), 3.71(2H, d, J8.3 Hz, CH2P), 4.17(6H, m, 2×CH2CH3 +CH2OCH2P), 5.28(2H, m, CH2 =CH), 5.88(1H, m, CH2 =CH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:33][CH2:34][O:35][CH2:36][CH2:37]Cl.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([C:18]2[N:17]=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([N:1]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)=[O:15])[CH:21]=[CH:20][CH:19]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(N)cc4)CC3)n2)cc1OC
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(N5CCOCC5)cc4)CC3)n2)cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a DMF (3 ml) solution of 355 mg of 1-(4-aminophenyl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazine were added 130 mg of 1-chloro-2-(2-chloroethoxy)ethane, 77 mg of sodium iodide and 249 mg of potassium carbonate, followed by overnight stirring at 100° C. After cooled to room temperature, the reaction solution was concentrated under reduced pressure and then water was added thereto, followed by extraction with chloroform. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then crystallization was carried out from ethanol-diethyl ether to obtain 210 mg of 4-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl)phenyl)morpholine as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][N:12](C=O)C>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:4][C:3]1[C:5]([Cl:10])=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[C:11]#[N:12]
Reactant: Nc1c(Cl)cc(F)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: O
Product: N#Cc1cc(F)cc(Cl)c1N
Temperature: 80 °C
Yield: 72 %

Procedure:
A mixture of 2-bromo-6-chloro-4-fluoroaniline (6.0 g, 26.7 mmol), zinc cyanide (11.42 g, 97.6 mmol) and Pd(PPh3)4 (2.16 g, 1.92 mmol) in anhydrous DMF (84 mL) was heated at 80° C., under an atmosphere of argon for 24 hours. The reaction mixture was cooled and diluted with brine. This mixture was extracted with ethyl acetate (×3) and the combined organic layers were washed with water (×2), dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a pale yellow solid (3.29 g, 72% yield). 1H NMR (300 MHz, CDCl3): δ 7.27 (dd, J=7.9, 2.9 Hz, 1H), 7.08 (dd, J=7.6, 2.9 Hz, 1H), 4.67 (br s, 2H).
Reaction SMILES: [S:1](=[O:30])(=[O:29])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH:23]CCCC)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].[Si](I)(C)(C)C>>[S:1](=[O:29])(=[O:30])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH2:23])=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: C[Si](C)(C)I
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CC=C2C(N)=O

Procedure:
Compound 11o was synthesized in a similar manner as 11a except that TMS-I was used in place of BBr3. Compound 11o was prepared from compound 12. EI-MS m/z 376 M+; 1H NMR (300 MHz, DMSO-d6) δ 0.88 (s, 3H, CH3), 6.44 (brs, 1H, 16-CH), 6.74(brs, 2H, CONH2), 6.97 (s, 1H, ArH), 7.01 (d, 1H, J=9 Hz, ArH), 7.32 (d, 1H, J=9 Hz, ArH), 7.89 (s, 2H, SO2NH2).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](OC)=[CH:13][C:12]=1OC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)c2ccccc2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
N-benzoyl-2,4-dimethoxybenzylamine (100 mg, 0.37 mmol) was dissolved in 1 ml 95% (v/v) trifluoroacetic acid (TFA) and stirred for 1 h at 20° C. TFA was removed by blowing with N2 and the residue suspended in methanol (1 ml). The reaction mixture was analyzed by TLC using CH2Cl2 /MeOH/AcOH (85:10:5) as eluent and the generated benzamide was determined quantitatively by HPLC using benzamide standard chromatograms.
Reaction SMILES: [Cl-:1].[Li+].[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@H:17](Br)[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4].O>CN(C)C=O>[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@@H:17]([Cl:1])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@H](Br)C[C@H]3[C@@H]1CC2
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@@H](Cl)C[C@H]3[C@@H]1CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of lithium chloride (1.3 g, 31 mM) in 9 ml of anhydrous dimethylformamide is heated to 70° and then cooled to room temperature. 1-Acetoxy-16α-bromo-3-methoxyestra-1,3,5(10)-trien-17-one (0.50 g) is added to the solution as a solid using Gooch tubing. The resulting suspension is heated to 50° to effect solution. The solution is then stirred at room temperature for 5 hr, poured into 100 ml of H2O, filtered and dried in vacuo to give a white solid. Recrystallization from methanol gives 1-acetoxy-16β-chloro-3-methoxyestra-1,3,5(10)-trien-17-one, yield 0.40 g (89%); m.p. 164°-166°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.Cl.[CH2:10]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][CH:11]1[OH:19].C(N(CC)C(C)C)(C)C.CN(C=O)C>C(#N)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH2:17][CH2:18][C:13]3([CH2:10][CH:11]([OH:19])[CH2:12]3)[CH2:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OC1CC2(CCNCC2)C1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OC1CC2(CCN(c3ccc(Br)cn3)CC2)C1
Temperature: 95 °C

Procedure:
0.24 g (1.35 mmol) of 5-bromo-2-fluoropyridine, 0.20 g (1.13 mmol) of 7-azaspiro[3.5]nonan-2-ol hydrochloride (JP 2003246780) and 0.51 g (3.94 mmol) of N,N-diisopropylethylamine in 3 mL of acetonitrile are placed in a sealed tube. 1 mL of DMF is added and the mixture is then heated at 95° C. for 12 hours. The reaction mixture is allowed to cool to room temperature and is then taken up in ethyl acetate and water. The aqueous phase is separated out and the combined organic phases are then washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. After purification by chromatography on silica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.138 g pure product is thus obtained in the form of a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[NH2:24][C:25]([CH3:41])([CH2:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[CH2:11][C:12]([NH:24][C:25]([CH3:41])([CH2:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)CC(=O)O)cc1
Reactant: CCOC(=O)C(C)(N)CC(=O)c1ccc(C)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC(=O)Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
To a solution of Intermediate 6B (0.388 g, 1.855 mmol) in DCM (10 mL) under argon was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.293 g, 2.192 mmol) and the reaction mixture was stirred at rt for 20 min. A solution of Intermediate 102B (0.4204 g, 1.686 mmol) in DCM (1.000 mL) followed by pyridine (0.409 mL, 5.06 mmol) were added and the reaction mixture was stirred at rt for 2.5 h. The reaction mixture was concentrated to give a dark oil which was dissolved in EtOAc (15 mL) and washed with water (5 mL). The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (80 g silica gel) to provide the desired product (0.650 g, 88%) as an orange oil. LCMS Anal. Calc'd for C24H28N2O6 440.19, found [M+H] 441.2. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.25 Hz, 2H), 7.24 (d, J=7.98 Hz, 2H), 4.14 (dd, J=7.15, 2.75 Hz, 2H), 3.65 (d, J=17.61 Hz, 1H), 3.20 (d, J=17.61 Hz, 1H), 2.40 (s, 3H), 2.18-2.27 (m, 2H), 1.39 (s, 3H), 1.19 (t, J=7.01 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=O.[CH3:18][C:19](=O)[CH2:20][C:21](=[O:23])[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:18][C:19]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:20]=1[C:21](=[O:23])[CH3:22]
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCCC2
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1cccs1)CCCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-thiophen-2-yl-methanone (the preparation of which is described in example 6) in 1.5 ml acetic acid was added 0.020 ml (0.21 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 46 mg (74%) 1-(2-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a yellow oil. ES-MS m/e (%): 328 (M+H+, 100).