Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([CH3:19])([CH2:17][NH2:18])[CH2:13][N:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:15][N:14]([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:11])[CH2:17][NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)CC(C)(C)CN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(C)(C)CNc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 101.1 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (353 mg, 2.5 mmol) in DMSO (5 mL) is added 2,2,N*1*,N*1*-Tetramethyl-propane-1,3-diamine (391 mg, 3 mmol), followed by Hunig's base (0.65 mL, 3.8 mmol). The reaction flask is sealed and heated to 80° C. for 16 h. The reaction is cooled to room temperature, is poured over ice water and is extracted with CH2Cl2. The organic layer is washed with water, brine, is dried (Na2SO4) and concentrated to afford the title crude compound (635 mg, crude) as an orange oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]#[N:13])=[CH:7][N:6]=1)=O.[NH3:14]>CO>[C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]([NH2:14])=[O:2])=[N:6][CH:7]=1)#[N:13]
Reactant: COC(=O)c1ncc(C#N)cc1C
Reactant: N
Solvent: CO
Product: Cc1cc(C#N)cnc1C(N)=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 5-cyano-3-methylpyridine-2-carboxylic acid methyl ester (1 g, 5.6 mmol) in methanol (5 mL) was added ammonia (4 mL, 28 mmol, 7N solution in methanol). The mixture was then heated at 50° C. with stirring in a sealed tube. After 60 min, HPLC analysis revealed completion of reaction. The mixture was concentrated in vacuo to give the title compound as a pale yellow solid: ESIMS: 162; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.87 (d, 1H), 8.30 (d, 1H), 8.09 (br s, 1H), 7.74 (br s, 1H), 2.50 (s, 3H)
Reaction SMILES: N([O-])=O.[Na+].C[O:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)=[CH:14][C:13]=1N.[ClH:30]>O>[C:18]12([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][C:7]([OH:6])=[O:29])=[C:13]([Cl:30])[CH:14]=3)[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: Cl
Reactant: COC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.00 g of sodium nitrite in 5 ml of water is added dropwise, whilst stirring, to a suspension of 5 g of 4-[4-(1-adamantyl)-2-amino-phenoxy)-butyric acid methyl ester in 10 ml of concentrated hydrochloric acid and 30 ml of water. After completion of the addition, the mixture is stirred for a further 3 hours at 0°C. The reaction solution is then filtered cold. The filtrate, kept at 0°C, is then added in portions to a solution of 5 g of freshly prepared copper-(I) chloride in 20 ml of concentrated hydrochloric acid at 0°C, whilst stirring. After completion of the addition, the temperature is allowed to rise to about 25°C and the mixture is then heated on a water bath until the evolution of nitrogen has ceased. It is then filtered, the residue is well rinsed with methylene chloride, and the filtrate is partitioned between 3 times 50 ml of methylene chloride and 50 ml of water. The organic phases are combined and evaporated in vacuo. The evaporation residue is dissolved in 100 ml of ethanol and 20 ml of 2 N sodium hydroxide solution and the mixture is left to stand for 24 hours at about 25°C. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 150 ml of 2 N hydrochloric acid and twice 50 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 100 g of silica gel, with ether as the migrating agent, and subsequent crystallisation from ethanol, gives 4-[4-(1-adamantyl)-2-chloro-phenoxy]-butyric acid of melting point 164°-166°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]([CH3:21])=[CH:16][C:17]([O:19]C)=[O:18])[CH:8]=[CH:7][C:6]=2[C:5]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]([CH3:21])=[CH:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:7][C:6]=2[C:5]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)C=C(C)C#C[Se]c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C#C[Se]c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1)=CC(=O)O

Procedure:
In a manner similar to that of Example 1g, by reacting 0.23 g (0.5 mmol) of methyl 5-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanyl)-3-methylpent-2-en4-ynoate with 0.23 g (5.5 mmol) of lithium hydroxide monohydrate, a pale yellow solid is obtained (0.05 g; yield=23%; m.p.=166° C.).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]4=[CH:20][CH:21]=[C:22]([C:23]5[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=5)[N:16]4[N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:54][S:55]([CH2:58][CH2:59][NH2:60])(=[O:57])=[O:56].Cl.Cl.CN(C)CCCN=C=NCC>>[CH3:54][S:55]([CH2:58][CH2:59][NH:60][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:22]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][CH:11]=4)=[N:15]3)=[CH:20][CH:21]=2)=[CH:24][CH:25]=1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)CCNC(=O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 30 mL vial, 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzoic acid (104 mg, 0.251 mmol), N,N-Dimethylformamide (2.08 mL, 26.9 mmol; Supplier=EMD), 1-Hydroxybenzotriazole (41 mg, 0.30 mmol), 4-Methylmorpholine (33.1 uL, 0.301 mmol), [B] 2-Methanesulfonyl-ethylamine; hydrochloride (0.0601 g, 0.376 mmol), and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0577 g, 0.301 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was partitioned with sat'd NaHCO3. The precipitate was filtered and washed with water to afford N-(2-Methanesulfonyl-ethyl)-4-[2-(4-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzamide as a yellow solid. MP 241-242° C. LCMS (E/I+) 521.00M+H). NMR 1H (DSMO-d6)-9.34 (d, 1H, J=2.00), 8.97 (s, 1H), 8.60 (d, 1H, J=8.21 Hz), 8.79 (t, 1H, J=5.72 Hz), 8.34 (d, 2H, J=8.52 Hz), 7.97 (d, 2H, J=8.52 Hz), 7.65 (d, 2H, J=9.00 Hz), 7.28 (d, 1H, J=4.80 Hz), 6.94-7.00 (m, 3H), 3.65-3.80 (m, 6H), 3.41 (t, 2H, J=6.88 Hz), 3.03-3.12 (m, 7H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH3:14].CN(C)[CH:25]=[O:26]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[S:19][C:20]([CH:25]=[O:26])=[CH:21][CH:22]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cccs1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A solution of diisopropylamine (0.588 mL, 60 mmol) in THF (20 mL) under N2 is cooled to −78° C. and treated with n-butyllithium (2.5 M in hexanes, 1.66 mL). The mixture is then warmed to 0° C. for 10 min, cooled back to −78° C., treated dropwise with a solution of thiophene-2-carboxylic acid ethyl ester (0.5 g, 3.2 mmol) in THF (12 mL), and stirred 5 min. N,N-dimethylformamide (0.324 mL, 4.16 mmol) is then added, and the reaction is allowed to warm to rt, while stirring overnight. Aqueous buffer (pH=7) is added, and the product is extracted into ethyl acetate (3×). Combined organic layers are dried, filtered, and concentrated. The resulting residue is applied to silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% to give 5-formyl-thiophene-2-carboxylic acid ethyl ester (325 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][C:12]3[N:13]=[C:14]([NH2:23])[N:15]=[C:16](S(C)(=O)=O)[C:17]=3[N:18]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1>[NH2:23][C:14]1[N:15]=[C:16]([N:43]2[CH2:44][CH2:45][N:40]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:46]=[CH:47][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:41][CH2:42]2)[C:17]2[N:18]=[C:10]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[S:11][C:12]=2[N:13]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: CC(c1ccc(F)cc1)c1nc2c(S(C)(=O)=O)nc(N)nc2s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(c1ccc(F)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 70 °C
Yield: 67.8 %

Procedure:
To a solution of 2-(1-(4-fluorophenyl)ethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.14 mmol) and triethylamine (30 μl, 0.21 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (51 mg, 0.21 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling down to room temperature, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) furnishing the title compound as a white solid (50 mg, 67%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29]([NH2:31])=[NH:30])=[NH:27])=[CH:21][CH:20]=1>C(O)C>[ClH:15].[NH2:31][C:29]1[NH:28][C:26]([NH:25][CH2:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:33][CH:32]=2)=[N:27][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:30]=1
Reactant: COc1ccc(CCNC(=N)NC(=N)N)cc1
Reactant: CCCCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCC1N=C(N)NC(NCCc2ccc(OC)cc2)=N1

Procedure:
100 ml of ethanol, 8.8 ml (37.1 mmol) of 1-tridecanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.4 mmol) of N1-(4-methoxyphenethyl)-biguanide hydrochloride, and the mixture was refluxed for 22 hours. The solvent was distilled of f under reduced pressure, and the residue was purified by silica gel column chromatography. The first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 70% aqueous acetonitrile to obtain 0.92 g of colorless crystals (1) having a melting point of 100 to 102° C., and the second main eluate was recrystallized from 70% aqueous acetonitrile to obtain 1.1 g of colorless crystals (2) having a melting point of 165 to 170° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])C1C=CC=CC=1NC(=O)OC(C)(C)C.FC(F)(F)O[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH2:31][C:32]([O-:34])=[O:33])=[CH:25]2.[Li+:37].CC(C)([O-])C.[K+]>>[F:1][C:2]([F:18])([F:17])[C:29]1[CH:30]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][C:26]([CH2:31][C:32]([O-:34])=[O:33])=[CH:25]2.[Li+:37]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(F)(F)F
Reactant: O=C([O-])Cc1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li+]
Product: O=C([O-])Cc1cc2cccc(C(F)(F)F)c2[nH]1

Procedure:
The titled compound was prepared from tert-butyl 2-(trifluoromethyl)phenylcarbamate using the procedures described in Example 26, Steps 26b through 26h, except for the use of potassium tert-butoxide instead of potassium hexamethyldisilizane in step 26g. MS (ES+) detects free acid at 244 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,6-dichloro-pyrimidine (20.93 g, 140 mmol) and sodium thiomethoxide (10.3 g, 147 mmol) in THF (100 mL) was stirred at room temperature for 16 h, then the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine, then dried over sodium sulfate and concentrated. The crude product residue was purified by recrystallization from hexanes (60 mL) to afford the title compound. The mother liquor was concentrated and the residue was purified by silica gel flash chromatography (0% to 10% ethyl acetate in hexanes as eluant) to afford additional title compound containing a small amount of byproduct 4,6-bis methylthio-pyrimidine. 1H NMR 400 MHz (CDCl3) δ 8.72 (s, 1H), 7.21 (s, 1H), 2.58 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([CH3:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([Zn]I)[CH:27]=[CH:28][CH:29]=1>O1CCCC1>[F:23][C:24]1[CH:29]=[C:28]([C:7]2[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([CH3:17])=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)c1cc(C)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: Fc1cccc([Zn]I)c1
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)c2cccnc2c1-c1cccc(F)c1
Temperature: 60 °C
Yield: 54 %

Procedure:
To a mixture of 7-acetyl-5-methylquinolin-8-yl trifluoromethanesulfonate (0.833 g, 2.50 mmol) in tetrahydrofuran (20 mL), with stirring, was added 0.5 M (3-fluorophenyl)(iodo)zinc in THF (10.0 mL, 5.0 mmol), followed by tetrahydrofurantetrakis(triphenylphosphine)palladium(0) (289 mg, 0.250 mmol). The reaction mixture was heated at 60° C. overnight, cooled to room temperature and quenched with sat. sodium bicarbonate. The mixture was filtered through a Celite pad. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified on silica gel, eluting with 0 to 80% ethyl acetate in hexane, to give the desired product (0.379 g, 54%). LCMS calculated for C18H14FNO (M+H)+: m/z=280.1; Found: 280.0.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](O)(=[O:25])C>CO>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]([O:25][CH3:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)c2nc(SCc3ccccc3)nn12

Procedure:
2-Benzylthio-5,8-dichloro[1,2,4]triazolo[1,5-a]pyridine (6.0 g, 0.019 mol) and 25 percent sodium methoxide in methanol (26.5 mL, 6.3 g, 0.116 mol) were combined in methanol and the mixture was heated to reflux for 2 hours. The mixture was then cooled, acidified with acetic acid, and concentrated by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the solution was washed with water and concentrated by evaporation under reduced pressure. The residue was triturated with hexane and the resulting solids were collected by filtration and dried to obtain 5.76 g (99 percent of theory) of the title compound as a light tan powder melting at 90°-91° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1Cl)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]([NH:17][CH3:18])[CH3:16])[N:14]=1)=[O:8].[F:23]C1C=C(C=CC=1)CN=C=O>>[F:23][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]([NH:17][CH3:18])[CH3:16])[N:14]=1)=[O:8]
Reactant: O=C=NCc1cccc(F)c1
Reactant: CNC(C)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Product: CNC(C)c1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
The 1-(3-fluorobenzyl)-3-(4-(1-(methylamino)ethyl)thiazol-2-yl)urea was prepared following the same procedure described for Intermediate 10a using 3-fluoro-benzyl isocyanate in step one.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:16])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:16]
Reactant: [N-]=[N+]=NC1CCc2cc(F)ccc2NC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1CCc2cc(F)ccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
3-Azido-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (3.36 g, 15.3 mmol) (Step C) dissolved in dry tetrahydrofuran was treated with 4.00 g (15.3 mmol; leq) of triphenylphosphine and the resulting solution stirred at room temperature under nitrogen for 2 hours. Water (0.48 mL, 2eq) was added and the mixtured stirred at room temperature for 16 hours. Solvents were removed under vacuum and the residue purified by preparative HPLC on silica, eluting with methylene chloride/methanol (9:1) to afford 2.39 g (12.3 mmol, 81%) of product. 1H NMR (200MHz, CD3OD): 1.87 (m,1H), 2.41 (m,1H), 2.6-2.9 (m,2H), 3.30 (dd;8,12 Hz;1H), 7.0 (m,3H). FAB-MS: calculated for C10H11FN2O 194; found 195 (M+H,100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]([F:34])([F:33])[C:19]([CH3:32])([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:20][NH2:21].CCN(C(C)C)C(C)C>>[NH2:1][C:2]1[C:3]([C:14]([NH:21][CH2:20][C:19]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)([CH3:32])[C:18]([F:34])([F:33])[F:17])=[O:16])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Reactant: COc1ccc(CNC(C)(CN)C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(C)(CNC(=O)c2nc(OC)c(C(F)(F)F)cc2N)C(F)(F)F)cc1

Procedure:
The title compound was prepared analogously to Example 1 from 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D) and 3,3,3-trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine (Intermediate N). DIPEA was used in this reaction. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (1H, m), 7.68 (1H, s), 7.25 (2H, d), 6.83 (2H, d), 6.70 (2H, s), 3.85 (3H, s), 3.75 (2H, m), 3.72 (3H, s), 3.70 (1H, m), 3.47 (1H, m), 2.80 (1H, t), 1.24 (3H, s)
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:42][CH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:42][CH2:43][C:44]4[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=4)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CNC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CC(C(=O)N2CCC(N3CCOCC3)CC2)=Cc2ccccc2-4)cn1
Yield: 93.2 %

Procedure:
A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), 2-(aminomethyl)-5-methylpyrazine (12 mg, 0.1 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. for 20 h, at which point it was introduced directly to silica gel and chromatographed (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow foam, which was triturated with Et2O and dried to give the title compound as a pale yellow solid (43 mg, 90% yield). LC/MS (ESI) retention time: 1.69 min, m/z 659 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.28-1.44 (m, 3 H) 1.46-1.59 (m, 1 H) 1.61-1.70 (m, 1 H) 1.71-1.81 (m, 2 H) 1.85-1.96 (m, 1 H) 1.97-2.13 (m, 3 H) 2.29 (t, J=10.45 Hz, 1 H) 2.35-2.46 (m, 4 H) 2.55 (s, 3 H) 2.61-2.77 (m, 2 H) 2.77-2.89 (m, 2 H) 3.62 (s, 4 H) 4.38 (s, 1 H) 4.78 (d, J=5.04 Hz, 2 H) 5.00-5.18 (m, 1 H) 6.81 (s, 1 H) 7.32-7.40 (m, 2 H) 7.40-7.50 (m, 3 H) 7.51-7.59 (m, 1 H) 7.88 (d, J=8.56 Hz, 1 H) 8.01 (s, 1 H) 8.39 (s, 1 H) 8.56 (d, J=1.01 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 21.18, 26.21, 27.03, 28.08, 33.26, 36.73, 41.91, 42.60, 49.52, 61.59, 67.07, 108.98, 116.90, 120.03, 121.21, 126.98, 127.94, 128.21, 129.27, 130.96, 131.23, 133.27, 134.01, 135.18, 135.25, 136.39, 142.94, 143.40, 149.41, 152.50, 168.10, 168.87.
Reaction SMILES: N[C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1Cl)=[O:3].I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=[C:15]([C:6]3[CH:5]=[C:4]([CH2:2][OH:3])[CH:9]=[CH:8][CH:7]=3)[C:23]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: NC(=O)c1ccc(B(O)O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(CO)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 48.9 %

Procedure:
A solution of (4-Aminocarbonyl-3-chlorophenyl)boronic acid (16 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA32 (9.7 mg, 42% yield). ESI-MS (M+H)+ m/z calcd 331.1, found 331.1.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1>Br>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Product: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reaction time: 1.5 h

Procedure:
Combine (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (31.5 g, 79.4 mmol) and 48% hydrobromic acid (250 mL). Heat to reflux. After 1.5 hours, cool and evaporate in vacuo to give a residue. Add water and sodium hydroxide (60 g) and extract with chloroform. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a solid. Collect the solid by filtration and recrystallize from hexane/chloroform to give, after drying, the title compound: mp; 212-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O>C(O)C.C(OCC)(=O)C.[Ni]>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:14]
Reactant: N#Cc1cccc2c(N)c([N+](=O)[O-])ccc12
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cccc2c(N)c(N)ccc12

Procedure:
A solution of 0,7 g (3,3 mmol) 1-amino-5-cyano-2-nitronaphthalene in a mixture of 75 ml ethanol and 75 ml ethyl acetate was hydrogenated at atm. pressure by using ca. 1 g Ra-Ni as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give 1,2-diamino-5-cyanonaphthalene as yellow crystals. IR (KBr): 2220 cm-1 (nitrile function).