Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Na+].[I-:28].CNCCNC.O1CCOCC1>CCOC(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([I:28])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c2cc(I)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A mixture of 5-bromo-3-chloro-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (2.80 g, 6.44 mmol) (prepared in accordance with the procedure described in Example 35, Method 1, step (b)), CuI (122 mg, 0.64 mmol), NaI (1.94 g, 12.9 mmol), N,N′-dimethyl-1,2-diaminoethane (142 μL, 1.28 mmol) and 1,4-dioxane (10 ml) was stirred at 120° C. for 24 h. The mixture was cooled to room temperature and diluted with EtOAc (200 ml). The combined organic phase was washed with diluted NH4OH solution (2×200 mL), HCl (0.1 N solution; 2×200 mL), brine (100 mL) and dried over Na2SO4. Filtration and concentration of the organic phase gave the sub-title compound (3.02 g 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)Nc1cc(F)ccc1N
Reaction time: 8 h
Yield: 70.8 %

Procedure:
(5-Fluoro-2-nitrophenyl)isopropylamine (2.1 g, 12.6 mmol) was dissolved in EtOAc (60 mL) and the flask evacuated and flushed with nitrogen gas, prior to the addition of 10% Pd/C (0.21 g). The mixture was stirred under an atmosphere of hydrogen gas overnight. A further amount of 10% Pd/C (0.21 g) was added and the mixture was stirred under an atmosphere of hydrogen for a further 3 h. A further amount of 10% Pd/C (0.21 g) was added and the mixture stirred under an atmosphere of hydrogen for a further 2 h. The resultant mixture was filtered through Celite® under an atmosphere of nitrogen and the filtrate concentrated in vacuo to afford the title compound as a dark red oil (1.5 g, 88%). 1H NMR (CDCl3, 400 MHz): δ 6.62 (1H, dd, J=8.34, 5.72 Hz), 6.36 (1H, dd, J=11.17, 2.77 Hz), 6.28 (1H, td, J=8.43, 2.75 Hz), 3.61-3.47 (1H, m), 1.24 (6H, d, J=6.27 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N[OH:15]>C(O)CCC>[OH:15][N:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: NO
Reactant: Nc1nc2ccccc2[nH]c1=O
Agent: Cl
Solvent: CCCCO
Product: O=c1[nH]c2ccccc2[nH]c1=NO
Temperature: 25 °C
Yield: 4.6 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973), was used. A mixture of 3-aminoquinoxalin-2(1H)-one (1) (100 mg, 0.620 mmol) and hydroxylamine hydrochloride (94 mg, 1.3 mmol; Aldrich Co.) in 5 mL of 1-butanol was heated to reflux. The resulting suspension was stirred under reflux for 12 h. The resulting suspension was cool to 25° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 5 mg (42%) of 3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one as a pale yellow solid mp dec.>330° C. 1H NMR (300 MHz, DMSO-d6) δ 11.156 (br s, 1H, NOH), 10.776 (br s, 1H, NH), 9.878 (br s, 1H, NH), 7.258-6.813 (m, H, H-5+H-6+H-7+H-8). LRMS: 177 (M+, 78%), 161 (100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH2:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[CH3:15]>ClCCl>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([CH2:14][CH3:15])[CH:17]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: CCc1cccc(N)c1
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(NC(=N)N(C)c2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-methylcyanamide (640 mg, 4 mmol) and m-ethylaniline hydrochloride (630 mg, 4 mmol) was placed in a pre-heated oil bath at 160° C. for 2.5 hours and then allowed to cool to room temperature. The resulting solid was taken up in dichloromethane and washed with 10% NaOH solution. The organic layer concentrated and the residue was flash chromatographed on SiO2 to give N,N'-di-(m-ethylphenyl)-N-methylguanidine (630 mg, 56%) as a colorless liquid:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[O:12][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCCCC1
Reactant: CC(=O)Nc1ccc(Br)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(Br)c(OCCN2CCCCC2)c1
Yield: 60.7 %

Procedure:
N-(4-Bromo-3-hydroxyphenyl)acetamide (19.4 g), anhydrous potassium carbonate (25.6 g), 1-(2 chloroethyl)piperidine hydrochloride (15.78 g) and acetone (400 ml) were heated at reflux for 18 h, filtered and evaporated to dryness to give the product as a solid (17.48 g).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[N:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:9]1[N:10]=[N:11][C:12]([Cl:14])=[CH:13][C:8]=1[N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1
Reactant: Clc1cc(Br)c(Cl)nn1
Reactant: C1=CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(N2CC=CCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
1,2,3,6-Tetrahydropyridine, (1.04 ml) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (2.0 g, 8.8 mmol) and potassium carbonate (2.4 g) in dry DMF (10 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 5 hours. The reaction was poured into water (100 ml) and extracted with ethyl acetate (×3). The combined extracts were washed with water (200 ml), brine, dried (MgSO4), filtered and evaporated. The residue was triturated with ether/petroleum ether to afford a white powder (1.96 g, 97%). 1H NMR (250 MHz, CDCl3) 6.82 (1H, s), 5.97 (1H, m), 5.80 (1H, m), 3.77 (2H, m), 3.59 (2H, m), 2.38 (2H, m). MS (ES+) 232 [MH]+.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=C[CH:9]=[C:10](OC(F)(F)F)[CH:11]=2)[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2].[NH:22]1C2=NC=CC=C2C(C(=O)C)=C1>>[C:1]([C:4]1[C:12]2[C:7](=[N:22][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ncccc12
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: CC(=O)c1cn(CC(=O)O)c2ncccc12

Procedure:
was prepared in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid from 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone [83393-46-8]. MS (UPLC/MS): 219.2 [M+H]+, 217.2 [M−H]−, 263.3 [M+HCOO]−, 435.3 [2M−H]−; tR (HPLC conditions f): 1.16 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.55 (bs, 1H), 8.49 (dd, 1H), 8.36 (dd, 1H), 7.31 (dd, 1H), 5.12 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: C(OC[O:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])C.CC(C)=O.Cl>O>[OH:5][C:6]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: CCOCOc1cc(C(F)(F)F)ccc1C=O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)cc1O
Temperature: 40 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A mixture of 1.90 g of 2-ethoxymethoxy-4-trifluoromethylbenzaldehyde, 10 ml of acetone, and 9 ml of 6 N hydrochloric acid was stirred at room temperature for 3 hours and subsequently at 40° C. for 1 hour. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture. This mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure, to obtain 1.05 g of 2-hydroxy-4-(trifluoromethyl)benzaldehyde.
Reaction SMILES: C(O)CO.[C:5]([CH:7]([C:12]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1)C(OC)=O)#[N:6].[OH-].[K+]>O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:12]1([CH2:7][C:5]#[N:6])[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: COC(=O)C(C#N)C1(c2ccccn2)CCOC2(CCCC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: N#CCC1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: 120 °C
Yield: 82.6 %

Procedure:
Ethylene glycol (300 ml) was added to methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.43 g, 49 mmol) followed by potassium hydroxide (5.5 g, 98 mmol), the resulting mix was heated to 120° C., after 3 h, the reaction mix was cooled and water (300 ml) was added, the product was extracted by Et2O (3×400 ml), washed with water (200 ml), dried (Na2SO4) and concentrated, the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 3% 2 CV; 3-25%, 12 CV; 25-40% 6 CV to give 2-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (10.37 g, 82% yield, m/z 257.0 [M+H]+ observed).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=3)=[CH:11][N:12]=[C:6]2[N:5]=1)(=O)[CH3:2].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:49]([NH2:52])(=[S:51])[CH3:50].C(OCC)C>C(Cl)(Cl)Cl>[F:27][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:7]3[CH:8]=[CH:9][C:4]([C:1]4[S:51][C:49]([CH3:50])=[N:52][CH:2]=4)=[N:5][C:6]3=[N:12][CH:11]=2)=[CH:18][C:17]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Reactant: CC(N)=S
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ncc(-c2ccn3c(-c4ccc(F)c(-c5ccccc5C#N)c4)cnc3n2)s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
5′-(7-Acetylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile (80 mg, 0.22 mmol) and pyridinium tribromide (110 mg, 0.34 mmol) in chloroform (5 ml) was stirred at 50° C. for 3 h. Thioacetamide (33 mg, 0.44 mmol) was then added and the reaction stirred at 50° C. for 16 h. The resulting mixture was partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by preparative thin-layer chromatography eluting with dichloromethane containing 5% methanol and 1% conc. ammonia to give a foam. Trituration with diethyl ether afforded 2′-fluoro-5′-[7-(2-methylthiazol-5-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid (10 mg, 11%): δH (400 MHz, DMSO) 2.75 (3H, s), 7.56-7.68 (5H, m), 7.81-7.92 (3H, m), 7.98-8.05 (2H, m), 8.40 (1H, s), 9.12 (1H, s); m/z (ES+) 412 (M++H).
Reaction SMILES: [NH:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[H-].[Na+].S([O:19][CH3:20])(OC)(=O)=O.[OH-].[Na+].[ClH:23]>CN(C)C=O.C1(C)C=CC=CC=1.O>[Cl:23][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]([CH3:2])[C:20](=[O:19])[CH2:3][CH2:4]2
Reactant: Cl
Reactant: COS(=O)(=O)OC
Reactant: O=C1CCC2CC=CC=C2N1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1C(=O)CCc2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 55 %

Procedure:
This tetrahydroquinolinone is dissolved in 100 ml of dimethylformamide/toluene (1:1); after addition of 1.8 g of sodium hydride (80% in paraffin oil), stirring is effected for 30 minutes at room temperature, followed by addition of 7.8 g of dimethyl sulphate and heating to 50° for 1 hour. After cooling of the mixture, 600 ml of water and 20 ml of 2 N sodium hydroxide solution are added; stirring is effected for 10 minutes, followed by acidification with 2 N hydrochloric acid. Extraction with ethyl acetate (4 times, with 300 ml each time), drying and concentration yield a solid residue which is recrystallised from ethyl acetate/petroleum ether (1:1) and yields 6.0 g (55% of theory) of 6-chloro-1-methyl-1,2,3,4-tetrahydroquinolin-2-one (m.p. 76°-78° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:17]1[CH:18]=[CH:13][N:14]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:16]=1
Reactant: Fc1cc(F)c2[nH]ccc2c1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(F)cc(F)cc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 5,7-difluoro-1H-indole and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting group with TBAF. Yield: 260 mg (63%).
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH2:7])=[O:6])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[CH3:1][C:2]1([C:5]([NH:7][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(C(N)=O)CC1
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
A −78° C. solution of 1-methylcyclopropanecarboxamide (1.35 g, 13.6 mmol) in THF (30 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1M THF, 17.7 mL, 17.7 mmol), stirred for 0.5 h, treated drop-wise with a solution of isopropenyl chloroformate (1.94 mL, 17.7 mmol) in THF (5 mL), stirred at −78° C. for 1 h, then allowed to warm to RT and stirred for 1 h. The mixture was quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford crude prop-1-en-2-yl (1-methylcyclopropanecarbonyl)carbamate (2.9 g, 116%) which was used without further purification.
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.[N:27]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37]/[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:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone and 2 equivalents of 4-(1-pyrrolidinyl-methyl)-aniline, melting point 45-50° C. in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17](O)[CH3:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:34]([CH:17]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:18])=[N+:35]=[N-:36]
Reactant: COc1ccc(C(C)O)cc1OCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(C(C)N=[N+]=[N-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. mixture of crude 1-(3-benzyloxy-4-methoxy-phenyl)-ethanol (10 mmol maximum) and diphenylphosphoryl azide (2.6 mL, 12 mmol) in toluene (18 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.6 mL, 11 mmol). The mixture is stirred at 0° C. for two hours and then at room temperature overnight. The reaction mixture is washed with water and concentrated to give 4-(1-azido-ethyl)-2-benzyloxy-1-methoxybenzene, which is used in the next step without purification.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:43])[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:31][CH:30]=1>C(Cl)Cl.CO>[CH3:41][N:40]([CH3:42])[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:43])=[O:39]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CN(CC(=O)N(C)C)Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(=O)N(C)C)cn3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide (Step 119.1), stirring the reaction mixture for 72 h at rt. The title compound: ESI-MS: 583.0 [M+H]+; tR=4.02 min (System 1); TLC: Rf=0.36 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:40](O)([CH3:42])[CH3:41]>S(=O)(=O)(O)O>[CH:40]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)O)cc1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 60 h

Procedure:
700 mg of (2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 100 ml of isopropanol and 15 drops of concentrated sulfuric acid was added. The reaction solution was boiled for 2.5 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 444 mg. MS (ES+): m/e=600.4 (M+H)+.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH:15](N)=[O:16]>O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH:14][CH:15]=[O:16]
Reactant: NC1CCc2c([nH]c3ccccc23)C1
Reactant: NC=O
Solvent: O
Product: O=CNC1CCc2c([nH]c3ccccc23)C1

Procedure:
A mixture of 8.90 g (0.048 mol) of 2,3,4,9-tetrahydro-1H-carbazol-2-amine and 65 ml of dry formamide was stirred and heated under N2 for 5 hr at 95°-100° C. The cooled reaction mixture was poured into H2O, and the precipitated gum extracted with CHCl3. The combined extracts were washed with 0.1 N HCl, 5% aqueous NaHCO3, and H2O, and dried. Et2O-trituration of the residue remaining after evaporation of the CHCl3 gave a tan solid, 8.58 g, mp 123°-126°. For analysis, it was necessary to dry the recrystallized (EtOH) sample at 120° (P2O5, 0.02 mm, 20 hr), mp 169°-171°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH:7][CH2:6][CH2:5]2
Reactant: c1c[nH]cn1
Reactant: O=C1CCCc2cc(Br)ccc21
Solvent: O=S(Cl)Cl
Product: Brc1ccc2c(c1)CCC=C2n1ccnc1

Procedure:
Analogously to Example 1, 2.25 g of 6-bromo-1-tetralone are reacted with 1.36 g of imidazole and 0.873 ml of thionyl chloride, yielding the title compound, which is purified by column chromatography (SiO2, hexane/ethyl acetate 9:1 to 1:1) and crystallisation from hexane/ether; m.p. 58°-64°, 1H-NMR (CDCl3): δ (ppm)=0.43 (m, 2H), 2.9 (m, 2H), 6.12 (t, 2H), 6.63 (d, 1H), 7.02 (d, 1H), 7.18 (d, 1H), 7.28 (dd, 1H), 7.36 (d, 1H), 7.61 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[CH:8]1.[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].Cl[C:28]1C(C(F)(F)F)=CC=CC=1C(O)=O>>[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[N:9][C:10]=2[C@@H:11]1[CH3:28])=[O:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: c1ccc(-n2cnc3c2CCNC3)nc1
Product: C[C@H]1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(Cl)c1Cl

Procedure:
The title compound was prepared in a manner analogous to Example 1, Step C substituting the product from Example 191, Step 3 for 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2,3 dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) mass calcd. C19H16Cl2N4O, 386.1. m/z found, 387.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.62-8.40 (m, 1H), 8.13-7.96 (m, 1H), 7.96-7.77 (m, 1H), 7.57-7.42 (m, 2H), 7.41-7.27 (m, 2H), 5.80 (t, J=8.0 Hz, 1H), 5.12-4.49 (m, 1H), 3.69-2.85 (m, 4H), 1.68-1.28 (m, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[O:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[C:17]1([C:15]2[O:14][C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[CH:16]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCc3oc(-c4ccccc4)cc3C2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(-c2cc3c(o2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.9 %

Procedure:
To a solution of 5-benzyl-2-phenyl-4,5,6,7-tetrahydrofuro[3, 2-c]pyridine (1.5 g, 0.00649 mol) in EtOH (30 mL) under nitrogen was added Pd—C(10%) (200 mg, 0.3 mmol). Hydrogen (1 atm) was applied and the reaction mixture was stirred for 3 to 4 h at RT. After consumption of starting materials as determined by TLC, the reaction mixture was filtered through Celite® (diatomaceous earth), washing with EtOH. The filtrate was concentrated to afford a solid which was washed with ether to afford 2-phenyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine (620 mg, 48%).