Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:26]#[C:25][C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:34])[CH3:35])=[CH:29][CH:28]=3)=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Product: CC(C)(O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1 method 2 step 2) (460 g, 1.0 mmol) and 2-(4-ethynyl-phenyl)-propan-2-ol (example D.4) (161 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (300 mg, 60%). MS (ISP) 490.2 [(M+H)+]; mp 170-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:15][CH3:16])([CH2:12][CH:13]=[CH2:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:24]Cl>CN(C)C=O>[CH3:32][O:31][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH3:19])[C:28]=1[O:29][CH3:30])[CH2:24][O:11][CH2:10][C@:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([NH:15][CH3:16])[CH2:12][CH:13]=[CH2:14]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: C=CC[C@](CO)(NC)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@](COCc1cc(OC)c(OC)c(OC)c1)(NC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Under argon, a solution of 2-(S)-(3,4-dichlorophenyl)-2-methylamino-4-penten-1-ol (8.5 g) in anhydrous N,N-dimethylformamide (50 mL) was added to a suspension of sodium hydride (1.5 g) in anhydrous N,N-dimethylformamide (50 mL) under cooling with ice, and the mixture was stirred for 1 hour at room temperature. A solution of 3,4,5-trimethoxybenzyl chloride (7.8 g) in anhydrous N,N-dimethylformamide (30 mL) was added to the reaction mixture under cooling with ice, and the resultant mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-water, extracted with ether, sequentially washed with water and saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 2:1→ethyl acetate), to thereby give the title compound (11.8 g, 81.8%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]([CH3:33])[C:27](=[O:32])[O:28][CH2:29][CH2:30][CH3:31])=[C:20]([F:34])[CH:19]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7](=[O:8])[NH:6][C:4]([C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:5])[S:25][N:26]([CH3:33])[C:27]([O:28][CH2:29][CH2:30][CH3:31])=[O:32])=[C:20]([F:34])[CH:19]=1
Reactant: CCCOC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: ClCCl
Product: CCCOC(=O)N(C)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 4 h

Procedure:
A solution of 2.0 g of 2,6-difluorobenzoyl isocyanate in 10 ml of dry methylene chloride was added rapidly to a stirred solution of 4.5 g of 32 in 20 ml of the same solvent at room temperature. After stirring for 4 hours the solvent was removed under reduced pressure, and the residue was purified by chromatography twice on silica, using first methylene chloride and then diethyl ether as eluent. The product thus obtained was finally purified by crystallization from diethyl ether/light petroleum to give 35, as colourless crystals, m.p.: 98°-99° C.
Reaction SMILES: I[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:12]=[N:11][C:5]3[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=3[CH:3]=2)=[CH:20][CH:19]=1)[CH3:14]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CNc2ncc(I)cc2N1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)NC(=O)CN3)cc1
Yield: 79 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (520 mg) was reacted with 4-ethoxycarbonylphenyl boronic acid as in General Procedure 4B to give the title compound as a light yellow solid in 79% yield. M.p.>200° C., LCMS: m/z=298.14 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.33 (3H, t, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 7.26 (1H, d, J=2.0 Hz), 7.67 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=8.1 Hz), 8.04 (1H, d, J=2.3 Hz).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[S:7]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 g of p-toluene sulfonyl chloride in 200 ml of toluene was slowly added to 50 g (0.505 mole) of L-alanine dissolved in 1 l 1N-sodium hydroxide cooled to below 5° C. and stirred at room temperature for 24 hours. Then, the aquose layer was cooled to below 5° C. and with a slow addition of concentrated hydrochloric acid, pH was adjusted to 1.5. After standing in the refrigerator for 3 to 4 hours, the white solid, so formed,.was filtered, washed with water sufficiently and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.O.CCOCC>C1C=CC=CC=1>[C:9]1([CH3:19])[CH:10]=[CH:11][C:12]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH2:19]([O:7][C:6](=[O:8])[C@H:2]([CH2:3][CH2:4][CH3:5])[NH2:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCC[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 180.6 %

Procedure:
A suspension of L-norvaline 1 (1.0 g, 8.53 mmol) benzyl alcohol (5 cm3) and p-toluenesulphonic acid (1.70 g, 8.96 mmol) was heated under reflux in benzene (25 cm3) with the removal of water (Dean-Stark trap) for 17 h (a solution resulted after 5 min). The solution was then cooled to room temperature and dry ether was added. Upon cooling to 0° C. a white solid precipitated and was collected by filtration, washed with dry ether and dried to give p-toluenesulphonate 2 (3.07 g, 95%) as a white solid: mp 142-144° C.; [α]D −1.45 (c 1 in dichloromethane); δH (200 MHz; CDCl3; Me4Si) 0.7 (3H, t, J 7.1, 5-H3), 1.09-1.37, (2H, m, 4-H2), 1.74, (2H, app. quartet, J 7.9, 3-H2), 2.30 (3H, s, Ar—CH3), 3.99 (1H, t, J 6.2, 2-H2), 4.98 (1H, d, J 12.3, OCHAHBPh), 5.11 (1H, d, J 12.3, OCHAHBPh), 7.07 (2H, d, J 8.0, 3′-H); 7.22-7.30 (5H, m, Ph-H) and 7.74 (2H, d, J 8.0, 2′-H); δC (50 MHz; CDCl3) 13.4 (CH3, 5-C), 17.9 (CH2, 4-C), 21.2 (CH3, Ar—CH3) 32.3 (CH2, 3-C), 53.1 (CH, 2-C), 67.6 (CH2, OCH2Ph), 126.0 (CH, Ph), 128.2 (CH, Ph), 128.3 (CH, Ph), 128.4 (CH, Ph), 128.7 (CH, Ph), 134.8 (quat., Ph), 140.2 (quat., Ph), 141.4 (quat., Ph) and 169.4, (quat., 1-C); m/z (FAB) 587.2777[M2.pTsOH.H+: (C12H17NO2)2.C7H8O3S.H requires 587.2791].
Reaction SMILES: C(OC1C=CC=C2C=1C=C(C(NC1C=CC(C3CCN(C(=O)CC(C)(C)C(O)=O)CC3)=CC=1)=O)N2CC)C.[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]([C:54]3[N:55]([CH2:65][CH3:66])[C:56]4[C:61]([CH:62]=3)=[C:60]([Cl:63])[C:59]([Cl:64])=[CH:58][CH:57]=4)=[O:53])=[CH:47][CH:46]=2)[CH2:41][CH2:40]1.[C:67]1(=[O:77])[C:71]2([CH2:75][CH2:74][CH2:73][CH2:72]2)[CH2:70][C:69](=[O:76])[O:68]1>>[Cl:63][C:60]1[C:59]([Cl:64])=[CH:58][CH:57]=[C:56]2[C:61]=1[CH:62]=[C:54]([C:52]([NH:51][C:48]1[CH:49]=[CH:50][C:45]([CH:42]3[CH2:41][CH2:40][N:39]([C:69](=[O:76])[CH2:70][C:71]4([C:67]([OH:77])=[O:68])[CH2:75][CH2:74][CH2:73][CH2:72]4)[CH2:44][CH2:43]3)=[CH:46][CH:47]=1)=[O:53])[N:55]2[CH2:65][CH3:66]
Reactant: CCn1c(C(=O)Nc2ccc(C3CCNCC3)cc2)cc2c(Cl)c(Cl)ccc21
Reactant: O=C1CC2(CCCC2)C(=O)O1
Agent: CCOc1cccc2c1cc(C(=O)Nc1ccc(C3CCN(C(=O)CC(C)(C)C(=O)O)CC3)cc1)n2CC
Product: CCn1c(C(=O)Nc2ccc(C3CCN(C(=O)CC4(C(=O)O)CCCC4)CC3)cc2)cc2c(Cl)c(Cl)ccc21

Procedure:
With a method similar to that used for the preparation of 4-(4-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidin-1-yl)-2,2-dimethyl-4-oxo-butyric acid, 1-[2-(4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}1-piperidin-1-yl)-2-oxo-ethyl]cyclopentanecarboxylic acid was prepared from 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and 2-oxa-spiro[4,4]nonane-1,3-dione. LCMS for C30H33Cl2N3O4 calcd. (m/e) 569, observed 570 (M+H).
Reaction SMILES: [F:1][C:2]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][C@@H:30]([C@@H:32]2[CH2:36][O:35]C(C)(C)[O:33]2)[CH3:31])[N:7]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][C@H:30]([CH3:31])[C@@H:32]([OH:33])[CH2:36][OH:35])[N:7]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO

Procedure:
A solution of tert-butyl 4-{[(2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidin-4-yl)amino]sulfonyl}piperazine-1-carboxylate (the product of step i) (0.23 g) in 10% trifluoroacetic acid/DCM (5 mL) was stirred at room temperature for 1 h. The mixture was evaporated to dryness in vacuo. The resulting crude oil was purified by reverse phase HPLC (75% to 5% gradient of 0.1% aqueous ammonium acetate in acetonitrile as eluent) to give the title compound as a white solid. Yield: 40 mg.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]([C@@H:36]1[CH2:40][C@@H:39](O)[CH2:38][N:37]1[S:42]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)(=[O:44])=[O:43])=[O:35].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CCOC(C)=O.CCCCCC.O>[CH3:32][O:33][C:34]([C@@H:36]1[CH2:40][C@H:39]([O:3][S:2]([CH3:1])(=[O:5])=[O:4])[CH2:38][N:37]1[S:42]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)(=[O:44])=[O:43])=[O:35]
Reactant: CS(=O)(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A biphasic solution of 13.9 ml (215 mmol) methanesulfonic acid, 29.8 ml (215 mmol) triethylamine and 58.7 g (224 mmol) triphenylphosphine in 150 ml toluene was added to a suspension of 60 g (179 mmol) (2S,4R)-4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 300 ml toluene which was stirred mechanically. After adding 44.9 ml (233 mmol) of diisopropyl azodicaboxylate (exothermic!) the solution was heated for 2.5 h at 80° C. 300 ml water was added at RT and extracted with ethylacetate (3×300 ml). The organic phase was washed with aqueous 10% KHSO4 (2×100 ml), 10% NaCl (2×150 ml), dried over Na2SO4 and evaporated to give 180 g of crude product. Flash chromatography (EtOAc/hexane 1:1) gave 63.7 g (86%) of (4S,2S)-4-Methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1)=[O:4]>CCO.C1COCC1>[CH3:1][N:2]([CH3:34])[C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)[C@H]1CC[C@H](n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1

Procedure:
Trimethylaluminium (1.50 mL; 3.0 mmol; 5.4 eq.) was added dropwise over 1 min to a solution of dimethylamine (2.50 mL; 5.0 mmol; 9.1 eq.) in DCE (50 mL) at 0° C. After 10 min, 4-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (prepared as described in example 62, step; 300 mg; 0.55 mmol; 1.0 eq.) in DCE (50 mL) was added dropwise over 5 min. The reaction solution was stirred for 16 h then a further portion of trimethylaluminium (10 mL; 20 mmol; 36 eq.) was added and the reaction solution refluxed for 4 h. The reaction mixture was then poured into ice-cold MeOH and concentrated under reduced pressure. The residue was redissolved in DCM, washed with 1 N HCl solution, Rochelle's salt solution and brine. Organic phase was finally dried over magnesium sulfate, filtered and concentrated to give the title compounds as a 3:1 mixture of cis and trans 4-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide (165 mg; 60%) in the form of a beige solid. HPLC (Chiralpak IC, EtOH:THF 90:10): Rt 6.61; 10.38 min (purity 76, 24%); MS (ESI+): 456.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[C:22]([O:32][CH3:33])[N:21]=3)[CH2:16][CH:15]2[C:34]([OH:36])=O)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].Cl.[CH3:38][NH:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH3:45].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:23]=[C:22]([O:32][CH3:33])[N:21]=3)[CH2:16][CH:15]2[C:34](=[O:36])[N:39]([CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45])[CH3:38])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: CCCCC=CNC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3ccccc3)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a ice cooled solution of the crude acid 13b (1.2 g, 1.81 mmol), N-methylhexeneamine hydrochloride (0.404 g, 2.7 mmol) and DIEA (1.2 g, 9.1 mmol) was added HATU (1.02 g, 2.7 mmol) and the mixture was stirred for twenty minutes on an ice bath and two hours at room temperature. A saturated solution of sodium hydrogen carbonate was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium hydrogen carbonate and brine and dried with sodium sulphate, filtered and evaporated under reduced pressure. The product was isolated by silica gel chromatography with hexane ethyl acetate, (0.8 g, 74%), (M+H)+591.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.[NH:17]1C=CN=[CH:18]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=3)[NH:6][CH:5]=2)[CH:16]=[CH:18][N:17]=[CH:1]1
Reactant: CN(C)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc2[nH]cc(Cn3ccnc3)c2c1
Yield: 93.5 %

Procedure:
A mixture of N,N-dimethyl-5-nitro-1H-indole-3-methanamine (J.Med, Chem, 9, 140,(1966)) (9.10 g) and imidazole (2.96 g) in xylene (120 ml) was heated under reflux for 2.5 hours and then cooled. The solid was filtered off, washed with ether and dried to give the title compound (9.40 g), m.p. 230°-232° C. (from ethyl acetate/methanol). Found: C,59.85; H,4.39; N,22.80. C12H10N4O2 requires: C,59.50; H,4.16; N,23.13%.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:16])[NH:7][C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2F)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[S:16][C:9]3[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=3[N:7]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=S)Nc2cc(F)ccc2F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nc3cc(F)ccc3s2)cc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution of 35.0 g of 4-methyl-2',5'-difluorobenzothioanilide in 80 ml of dimethylformamide was added dropwise to a suspension of 16.0 g of potassium tertbutoxide in 80 ml of dimethylformamide under ice cooling over the course of 15 minutes. The reaction mixture was heated, and reacted at 140° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and poured into 1500 ml of water. The preceipitated colorless crystalline power was collected by filtration, and dried to give 31.6 g of crude crystals of the captioned compound. Recrystallization from n-hexane gave the captioned compound as colorless plate-like crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[OH:11].P(Br)(Br)[Br:13]>C(OCC)C>[Br:13][CH2:8][C:7]1[C:2]([F:1])=[C:3]([OH:11])[CH:4]=[CH:5][C:6]=1[F:10]
Reactant: OCc1c(F)ccc(O)c1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Oc1ccc(F)c(CBr)c1F
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of 2,4-difluoro-3-(hydroxymethyl)phenol (step 1, 410 mg, 256 mmol) in diethyl ether (4 mL) and dichloromethne (1 mL) was added phosphorus tribromide (0.257 mL, 2.71 mmol) at 0° C. The mixture was stirred for 30 min, and then the mixture was poured onto ice-aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with water and brine, dried over magnesium sulfate and evapolated to afford 266 mg (47%) of the title compound as a colorless oil, which was used in the next step without purification:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:12][CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O.[CH3:24][C:25]1([CH3:37])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)[O:26]1>CN(C=O)C>[CH2:16]([O:15][CH2:14][CH:13]([CH3:23])[CH2:12][N:35]1[CH:36]=[C:32]([B:27]2[O:26][C:25]([CH3:37])([CH3:24])[C:29]([CH3:31])([CH3:30])[O:28]2)[CH:33]=[N:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(COCc1ccccc1)COS(C)(=O)=O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COCc1ccccc1)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (0.855 g, 6.18 mmol) and 3-(benzyloxy)-2-methylpropyl methanesulfonate (Compound 18F, 1.46 g, 5.67 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2 mmol) in DMF (4 mL) and the mixture was allowed to stir at 80° C. overnight. The reaction was quenched with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (2×30 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Teledyne ISCO Combiflash® Rf system using Heptane/EtOAc (70:30→30:70) as eluent to give the desired product as a light-yellow oil. 1H NMR (CDCl3, 400 MHz): δ=7.80 (s, 1H), 7.65 (s, 1H), 7.29-7.37 (m, 5H), 4.49 (s, 2H), 4.26, 4.04 (ABX, JAB=13.4 Hz, JAX=6.3 Hz, JBX=7.1 Hz, 2H), 3.32 (d, J=5.6 Hz, 2H), 2.41 (m, 1H), 1.33 (s, 12H), 0.95 (d, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][N:21]=1>CS(C)=O>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([O:18][C:20]4[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][N:21]=4)[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 60 mg, 1.5 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9 mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours, 6-chloro-N-methyl-nicotinamide (D10) (400 mg, 2.5 mmol) was added and the reaction mixture was heated to 120° C. for 6 hours. The reaction was allowed to cool and the crude mixture was applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were reduced in vacuo to afford the title compound (E121). 1H NMR (DMSO-d6) δ 8.56 (1H, dd, J=2.4, 0.4 Hz), 8.48 (1H, br m), 8.20 (1H, dd, J=8.4, 2.4 Hz), 7.16 (1H, d, J=8.0 Hz), 7.03 (1H, dd, J=8.4, 0.4 Hz), 6.91 (1H, d, J=2.4 Hz), 6.86 (1H, dd, J=8.0, 2.4 Hz), 2.87-2.77 (8H, m), 2.36 (4H, m), 2.00 (2H, m), 1.78 (2H, m), 1.58 (2H, m); MS (ES+) m/e 352 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].I[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:10][C:8]([NH:7][C@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C@H:4]([CH2:1]/[CH:2]=[CH:3]/[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: OCCCc1ccc(I)cc1
Reactant: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](C/C=C/c1ccc(CCCO)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of di-tert-butyl (4S)-4-allyl-N-(tert-butoxycarbonyl)-L-glutamate (940 mg, 2.53 mmol) in 5 mL acetonitrile under an argon atmosphere was added 3-(4-iodophenyl)propan-1-ol (740 mg, 2.82 mmol), triethylamine (394 μl, 2.82 mmol), and palladium(II) acetate (106 mg, 0.47 mmol). The mixture was stirred in a pressure tube at 80° C. for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure and the crude material was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.