Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15]COCC[Si](C)(C)C)[C:12]2[C:7](=[C:8]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[CH3:25][O:24][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)[CH:9]=1)[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:13]2=[O:15]
Reactant: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(N3CCCN(C)CC3)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)O)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a light brown solution of 6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.00 g, 2.10 mmol) in 18 mL 3:1:1 tetrahydrofuran:methanol:water was added lithium hydroxide monohydrate (0.267 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 5 hours, acidified to pH 4 with 1 N HCl, and stirred an additional 20 minutes. The reaction mixture was concentrated and dried under high vacuum to afford an orange foam. 1H NMR (300 MHz, DMSO, d6) δ 11.06 (s, 1 H, NH), 7.53 (s, 1 H, C═CH), 7.00 (d, 1 H, Jm=2.4 Hz, ArH5), 6.70 (d, 1 H, Jm=2.4 Hz, ArH7), 4.05-3.99 (m, 2 H, ArNCH2CH2CH2NCH3), 3.87 (s, 3 H, OCH3), 3.68-3.60 (m, 2 H, ArNCH2CH2NCH3), 3.54-3.47 (m, 2 H, ArNCH2CH2NCH3), 3.41-3.26 (m, 2 H, ArNCH2CH2CH2NCH3), 2.82 (d, 3 H, J=4.8 Hz, NCH3), 2.46-2.41 (m, 1 H ArNCH2CH2CH2NCH3), 2.30-2.25 (m, 1 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C17H21N3O4+H]+ Theor. m/z=332; Obs. 332.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([N:11]2[C:16](=[O:17])[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[S:12]2(=[O:23])=[O:22])[N:4]=1.[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([N:11]2[C:16](=[O:17])[N:15]([CH2:27][C:26]3[C:25]([F:24])=[CH:32][C:31]([F:33])=[CH:30][C:29]=3[F:34])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[S:12]2(=[O:23])=[O:22])[N:4]=1
Reactant: COc1cnc(N2C(=O)Nc3ccccc3S2(=O)=O)nc1OC
Reactant: Fc1cc(F)c(CBr)c(F)c1
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)nc1OC
Yield: 13.3 %

Procedure:
The title compound was prepared from 2-(4,5-dimethoxypyrimidin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA32) (50 mg, 0.15 mmol), 2,4,6-trifluorobenzyl bromide (41 mg, 0.18 mmol) and K2CO3 (62 mg, 0.45 mmol) in DMF (1.5 mL) using the methods of (115). After purification by gradient column chromatography further purification by preparative HPLC (method C) yielded the title compound (8 mg, 0.02 mmol).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH3:10])(=[O:8])[O:5]CC)[CH3:2].[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>>[CH2:1]([O:3][P:4]([CH2:9][CH3:10])(=[O:5])[O-:8])[CH3:2].[CH3:11][N+:12]1([CH2:9][CH3:10])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CCOP(=O)(CC)OCC
Reactant: Cn1ccnc1
Product: CCOP(=O)([O-])CC
Product: CC[N+]1(C)C=CN=C1
Reaction time: 1.33 h
Yield: 183.3 %

Procedure:
Diethylethanephosphonate (68.2 g, 99%, 0.406 mole) was dripped into a 300 ml flask containing 33.3 g (99%, 0.402 mole) N-methylimidazole at 160° C. under nitrogen and stirring over a period of 80 minutes. The liquid was stirred at the same temperature for an additional 10 hours. The liquid was cooled, moved to a rotary evaporator and dried at 140° C./5 mmHg for 2.5 hours. The product (92.4 g, yield 92%) was a liquid at room temperature. 1H-NMR (CDCl3, 300.13 MHz, δ): 10.99 (s, 1H, —N—CH═N—), 7.73 (s, 1H, —N—CH═CH—N—), 7.65 (s, 1H, —N—CH═CH—N—), 4.39 (q, 2H, —N—CH2—CH3), 4.09 (s, 3H, —NCH3), 3.92 (m, 2H, —O—CH2—CH3), 1.56 (m, 3H, —OCH2—CH3), 1.56 (m, 2H, —(O═)P—CH2—CH3), 1.19 (m, 3H, —(O═)PCH2—CH3), 1.19 (m, 3H, —NCH2—CH3). 31P-NMR (CDCl3, 81.015 MHz, δ): 25.57 [s, RO—(R)P(═O)—O−].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([NH2:22])=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:10][CH2:11][CH2:12]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(F)c(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C2(CCC2)O3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A mixture of di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (14.1 mg), 2-fluoro-5-methoxyphenylboronic acid (12.7 mg), PdCl2(PPh3)2 (5.3 mg) and 1M aqueous Na2CO3 (0.1 mL) in dioxane (0.4 mL) was stirred for 2 hours at 100° C. The mixture was filtered by using Chem Elut cartridges (Agilent Technologies) and washed with CHCl3. The filtrate was evaporated to give a brown oil. The oil was dissolved in toluene (0.5 mL) and to the mixture was added silicagel (neutral; 50 mg). The mixture was stirred for 1 hour at 100° C. The mixture was filtered and washed with CHCl3. The filtrate was evaporated. The residue was purified with HPLC (Column: Waters SunFire™ Prep C18 OBD™ 5 micrometer, 19×100 mm; MeOH/0.1% aqueous HCOOH 11/89 to 95/5(v/v)) and afforded 6′-(2-fluoro-5-methoxyphenyl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (1.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([NH2:19])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:22]([C:31]([F:34])([F:33])[F:32])=[N:23][N:24]([CH2:27][C:28](O)=[O:29])[C:25]=1[CH3:26].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:20][C:21]1[C:22]([C:31]([F:33])([F:32])[F:34])=[N:23][N:24]([CH2:27][C:28]([NH:19][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:29])[C:25]=1[CH3:26]
Reactant: Nc1cnn(-c2ccc(F)cc2)c1-c1ccccc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)Nc1cnn(-c2ccc(F)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-phenylpyrazol-4-amine (0.03 g, 0.12 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.024 g, 0.12 mmol), followed by diisopropylethylamine (0.031 g, 0.24 mmol) and HATU (0.055 g, 0.14 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.045 mmol, 28%). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.55 (s, 1H), 7.44-7.34 (m, 3H), 7.22-7.14 (m, 2H), 7.07-6.93 (m, 4H), 4.86 (s, 2H), 2.29 (s, 3H); MS: (ES) m/z calculated for C22H16ClF4N5O [M+H]+ 478.1, found 477.8.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=O.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](=[S:26])[NH2:25])=[CH:22][CH:21]=1.C(O)(C)C>CCO>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]2[S:26][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=3)[N:25]=2)=[CH:22][CH:21]=1
Reactant: NC(=S)c1ccc(Br)cc1
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Solvent: CC(C)O
Solvent: CCO
Product: CCCCCCCOc1ccc(-c2csc(-c3ccc(Br)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a stirring solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.37 g, 4.38 mmol) in EtOH (10 mL) were added 4-bromobenzothioamide (0.95 g, 4.38 mmol) and isopropanol (10 mL). The reaction mixture was stirred at room temperature for 16 h. The solid was isolated by filtration, washed with EtOH (5 mL) then taken up in DCM (10 mL) and NaHCO3 (20 mL) and stirred for 1 h at room temperature. The solid was isolated by filtration, washed with water (2×10 mL) and acetonitrile (2×4 mL) then dried to afford 1.02 g (52%) of 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole as a white micro-crystalline solid. LCMS-ESI (m/z) calculated for C22H24BrNOS: 429.1. found 430.0 [M+H]+, tR=3.20 min. (Method 4).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C.BrC1[S:45][C:46]2[C:52]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=1.Cl>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:45][C:46]4[C:52]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][CH:50]=[CH:49][C:47]=4[N:48]=3)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC)C3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (1g) (117 mg, 0.30 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for one hour. Following concentration under reduced pressure, the residue was dissolved in DMF (3 mL). Diisopropylethylamine (0.32 mL, 1.84 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (87 mg, 0.30 mmol) were added, and the mixture was stirred at 70° C. for two hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, ethyl acetate) to obtain 97 mg of the title compound as a pale yellow solid (65%).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[F-].[K+].[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([O:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: OC1CCCCC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(F)c(F)c(OC2CCCCC2)c(C#N)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A 5.0 g amount of tetrafluoroisophthalonitrile and 2.18 g of potassium fluoride were dissolved in 25 ml of acetonitrile, and 3.83 g of cyclohexanol was then dropwise added to the mixture. After the dropwise addition, the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the concentrated liquid was poured to 50 ml of water. The resultant mixture was extracted with carbon tetrachloride. After washing with water, the extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off. Thus, 6.2 g (88% yield) of the desired compound No. 47 was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.N1C=CC=CC=1.ClCCl>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1ccccc1Oc1cccnc1
Reaction time: 48 h
Yield: 5.9 %

Procedure:
2-Bromophenol (355 mg, 2.05 mmol), 3-pyridyl-boronic acid (500 mg, 4.1 mmol), copper acetate (745 mg, 4.1 mmol) and pyridine (3.3 mL, 41 mmol) were added to dichloromethane (41 mL) and stirred for about 48 hours under air. The reaction was diluted with water (50 mL) and the layers separated. The organic layer was washed with 5N NaOH. The organic layer was concentrated, and chromatographed on silica gel (MeOH/dichloromethane) to yield 3-(2-bromo-phenoxy)-pyridine (30 mg, 6%) as a yellow oil. MS found 249.1 M+1. 3-(2-Bromo-phenoxy)-pyridine was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+): 256.1 (M+1)
Reaction SMILES: [CH:1]1([N:5]2[C:10](=[O:11])[CH2:9][O:8][C:7]3[N:12]=[C:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:6]2=3)[CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[NH2:32][C:28]1([C:25]2[CH:24]=[CH:23][C:22]([C:13]3[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:15][C:6]4[N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:10](=[O:11])[CH2:9][O:8][C:7]=4[N:12]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCC3)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCC3)C(=O)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 43.8 %

Procedure:
tert-Butyl 1-(4-(1-cyclobutyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (31 mg, 0.059 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (11 mg, 35% yield). 1H-NMR (500 MHz, MeOD) δ 7.35-7.58 (5H, m), 7.25-7.35 (3H, m), 7.10-7.25 (2H, m), 4.80 (2H, s), 4.59 (1H, quin), 2.65-2.83 (2H, m), 2.40-2.65 (6H, m), 2.13-2.29 (1H, m), 1.79-2.02 (3H, m). LCMS (Method A) RT=4.58 min, M+2H+=427.21.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]([CH3:56])[O:54][CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]([CH3:56])[O:54][CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 103 from 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl ]-2-(2-triphenylmethyl-tetrazol -5-yl)-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:26](N)=[CH:25][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:28])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]=O.[C:31]([BH3-])#[N:32].[Na+].[NH4+].[Cl-]>C1COCC1.CC#N>[CH2:1]([O:8][C:9]1[C:26]([N:32]([CH3:31])[CH3:29])=[CH:25][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:28])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4cc(N)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a suspension of 3-benzyloxy-2-aminoestra-1,3,5(10)-trien-17-one (80, 0.751 g, 2.0 mmol) in THF (2.0 mL) and CH3CN (10 mL) were added 37% aqueous formaldehyde (4.0 mL) and sodium cyanoborohydride (0.377 g, 6.0 mmol) and stirred for 2 h at room temperature. Additional sodium cyanoborohydride (0.377 g, 6.0 mmol) was then added to the reaction mixture, which mixture was then stirred for 20 h. Next, saturated aqueous NH4Cl at 0° C., was added to the reaction mixture, and it was then extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:THF (5:1→3:1, v/v) to afford 0.797 g of 81 (99% yield) mp: 165-166° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=[C:17]3[S:21][C:20](SC)=[N:19][C:18]3=[O:24])[CH:14]=2)C=[CH:8][C:7]=1[C:25]#[N:26])[CH2:2][CH2:3][CH3:4].[CH:27]1([NH2:30])[CH2:29][CH2:28]1.C([N:34](C(C)C)CC)(C)C>>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[C:17]3/[C:18](=[O:24])[N:19]=[C:20]([NH:30][CH:27]4[CH2:29][CH2:28]4)[S:21]/3)[CH:14]=2)[N:26]=[CH:25][C:7]=1[C:8]#[N:34])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CC1
Reactant: CCCCOc1c(C#N)ccc2ccc(C=C3SC(SC)=NC3=O)cc12
Reactant: CCN(C(C)C)C(C)C
Product: CCCCOc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41c was used, starting from 1-butoxy-7-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-naphthalene-2-carbonitrile (example 79d), cyclopropylamine, and DIEA (diisopropylethylamine) to give 4-butoxy-6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 393 (MH+).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][CH:19]=[C:20]([CH:22]=O)[CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: CC(=O)N1c2ccc(-c3cc(C=O)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3cc(CN4CCCCC4)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(4-formyl-2-furanyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 20) (28 mg, 0.073 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with piperidine (8.65 μL, 0.087 mmol) and acetic acid (8.34 μL, 0.146 mmol) and stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (20.07 mg, 0.095 mmol) was added and the mixture was stirred again under nitrogen. After 16 hours reaction time the mixture was loaded onto a 2 g Flash SCX-column, eluting with MeOH (60 mL) followed by 2M MeOH/NH3 (60 mL). The product-containing fraction was evaporated to dryness to give a light brown solid (19 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[C:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:3]=1
Reactant: Cc1ccnc(C#CCNC(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
The residue of step A was dissolved in absolute ethanol (50 ml). The solution was flushed with argon, and a slurry of Pd/C (9.346 g, 0.325 mmol) in absolute ethanol (20 ml) was added. The resulting suspension was stirred in an athmosphere of hydrogen overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica, gradient of 1 to 5% methanol containing 7N ammonia in DCM) to yield 1.22 g (5.4 mmol, 84%, two steps). MS(ESI) m/z=251.2 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 86 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 1 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The orange residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 6:1) to give 107 mg (82%) of a white solid. MS (ISP) 429.6 (M+H)+.