Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[NH2:3][N:4]([CH2:9][CH2:10][OH:11])[C:5](=[O:8])[O:6][CH3:7].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:4]([C:5]([O:6][CH3:7])=[O:8])[NH:3][CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)N(N)CCO
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)N1CCOCN1
Temperature: 42 °C
Reaction time: 21 h
Yield: 85.8 %

Procedure:
At 22° C., 22.4 g (0.746 mol) of paraformaldehyde were added with stirring, over a period of 2 min to a mixture of 100 g (0.746 mol) of methyl N-amino-N-2-hydroxyethylcarbamate in 1500 ml of methylene chloride. After addition of 8.5 g (0.045 mol) of p-toluenesulfonic acid, the mixture was stirred at 42° C. for 21 h, until the precipitate had dissolved, and was then cooled to 20° C., and magnesium sulfate was added. The mixture was filtered and the filtrate was concentrated under reduced pressure. This gave 111.8 g of the title compound as a colorless resin with a GC purity of 85%, corresponding to a yield of 85.8% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:31][C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=O)[O:27]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 85.2 %

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) (245 mg, 0.75 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (190 mg, 0.825 mmol) according to the general procedure K. Obtained as a yellow oil (318 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>C(OCCO)C>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCOCCO
Product: COc1ccc2c(Nc3ccc4[nH]ccc4c3)c(C#N)cnc2c1
Temperature: 120 °C

Procedure:
Using an analogous procedure to that described in Example 141, 1.0 g (4.57 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile, 724.8 mg (5.48 mmol) of 5-aminoindole and 528.3 mg (4.57 mmol) of 5-aminoindole in 35 mL of 2-ethoxyethanol was heated at 120° C. for 2 hr. The work up gave 1.38 g of the product as a greenish gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 314.9 HRCIMS: calcd 314.117 for C19H14N4O (M+), obsd 314.1135.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:16])[CH:14]=[CH2:15].C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([CH2:15][CH2:14][CH:13]=[O:16])=[CH:3][CH:4]=1)[CH3:10]
Reactant: C=CCO
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CCC=O)cc1
Temperature: 77.5 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Ethyl 4-iodobenzoate (200 g, 0.725 mol) and allyl alcohol (63 g, 1.087 mol) are added to a stirred suspension of Sodium bicarbonate (152 g, 1.812 mol), tetrabutyl-ammonium bromide (117 g, 0.362 mol) and Palladium (II) acetate (3.2 g, 0.014 mol) in DMF (600 mL). The reaction mixture is warmed to 75-80° C. for 3-3.5 hours and cooled to 40° C.-50° C. Toluene (1 L) is added to the reaction mixture with vigorous agitation and the mixture is stirred for 15 min at room temperature. The resulting mixture is filtered through a celite pad. The pad is washed with toluene (2×200 mL). The filtrate and wash are combined, washed with water (3×1 L), evaporated to constant weight at 30° C.-40° C. and 10 mmHg. The crude product 147.5 g (98.8%, 84% by HPLC) of 4-(3-Oxo-propyl)-benzoic acid ethyl ester as dark brown oil is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@H:6]([NH:13][C:14](=[O:25])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]1=[O:24])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[N:27]1[C:36]2[NH:35][CH2:34][CH2:33][CH2:32][C:31]=2[CH:30]=[CH:29][C:28]=1[CH:37]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@H:6]([NH:13][C:14](=[O:25])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH:23][CH2:37][C:28]2[CH:29]=[CH:30][C:31]3[CH2:32][CH2:33][CH2:34][NH:35][C:36]=3[N:27]=2)[C:17]1=[O:24])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=Cc1ccc2c(n1)NCCC2
Reactant: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(N)c1=O)c1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(NCc2ccc3c(n2)NCCC3)c1=O)c1cccnc1
Reaction time: 48 h

Procedure:
To a solution of the amine 16-6 (155 mg, 0.433 mmol), the aldehyde 14-3 (70 mg, 0.433 mmol) in CH2ClCH2Cl was added crushed 4 Å seives, AcOH (20 μL) and then NaB(OAc)3H (184 mg, 0.866 mmol). After stirring for 48 hours, the mixture was filtered through celite, poured into EtOAc and washed with saturated NaHCO3 then brine. The dried (MgSO4) solution was concentrated in vacuo to give a foam type solid. Column chromatography (5% MeOH in CHCl3) afforded the title compound 16-7 as a foam type solid.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Si:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CI.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Si:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C@H:23]2[CH2:24][CH2:25][C@H:26]([C:29]([CH3:1])([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: COC(=O)C(C)[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of lithium diisopropylamide (12.9 mmol) in THF (20 mL) was added dropwise to a stirred solution of methyl 2-[trans-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-propanoate (4.42 g, 11.7 mmol) in THF (40 mL) at −78° C. under an argon atmosphere and the mixture was warmed to room temperature. The mixture was cooled to −78° C. and methyl iodide (0.92 mL, 14.7 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 20 h. Saturated aqueous ammonium chloride (100 mL) and ethyl acetate were added sequentially, both in one portion. The organic layer was separated and washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to leave an oil. The oil was purified by column chromatography, using a gradient of 0-15% ethyl acetate:isohexane was eluent, to give the title compound (4.0 g, 87%) as a colourless oil; 1H NMR δ 0.0 (6H, s), 0.8 (9H, s), 0.98 (6H, s), 1.0-1.1 (2H, m), 1.18-1.31 (2H, m), 1.45-1.56 (3H, m), 1.7-1.8 (2H, m), 2.15-2.28 (1H, m), 3.5 (3H, s), 6.55 (2H, d), 6.85 (2H, d).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C(O[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])C.[Cl-].[NH4+]>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:15]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[OH:16])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To magnesium turnings (6.08 g, 0.25 mole) and an iodine crystal in 600 ml of dry tetrahydrofuran (THF) (distilled from lithium aluminum hydride) and under an atmosphere of nitrogen was added dropwise a solution of p-bromofluorobenzene in 125 ml of THF. The temperature of the reaction mixture was kept below 10° C. by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hr. A solution of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester (24.7 g, 0.10 mole) in THF was added, and the mixture was stirred at room temperature for 17 hr. The reaction mixture was poured into an icy, aqueous solution of ammonium chloride, and the resulting solution was extracted with methylene chloride. The solution was extracted with dilute sodium hydroxide and was dried (magnesium sulfate). The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 19.87 g (51%) of title compound, m.p. 113°-115° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:9]=[C:10]([C:23]2[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:24]=2[C:25]([OH:27])=O)[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Si:40]([O:47][CH2:48][C@@H:49]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][NH:50]1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>>[Si:40]([O:47][CH2:48][C@@H:49]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][N:50]1[C:25]([C:24]1[CH:28]=[C:29]([CH:30]=[CH:31][C:23]=1[C:10]1[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:36][CH2:37][CH2:38][CH3:39])[N:9]=1)[C:32]([O:34][CH3:35])=[O:33])=[O:27])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CCCCN(CCCC)C(=O)c1cn(CCCN2CCN(C)CC2)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1Cc2ccccc2CN1
Product: CCCCN(CCCC)C(=O)c1cn(CCCN2CCN(C)CC2)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Yield: 93.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271H, 2-(4-(dibutylcarbamoyl)-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (110 mg, 0.2 mmol) and (S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline (73 mg, 0.26 mmol) were converted to the title compound (150 mg, 93%). MS(ESI+) m/z 802.4 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH:11]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH2:17][CH2:16]2)=[O:14])[N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]1[CH2:9][N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:11]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH2:19][CH2:20]2)=[O:14])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 102.7 %

Procedure:
{1-Benzyl-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidine-3-yl}carbamic acid tert-butyl ester (2 g, 4 mmol) was dissolved in 15 mL DCM/CF3COOH (2:1), stirred overnight. After removal of solvent, the residue was treated with saturated NaHCO3, extracted with EA (2×100 mL). The organic layer was dried over Na2SO4, concentrated to afforded title product 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile 1.6 g (100%) as brown oil. MS m/e=390.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1([CH2:26][CH3:27])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3.CO.[OH-].[K+]>O>[CH2:26]([C:5]1([CH2:4][C:3]([OH:28])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:14][CH:13]=3)[CH3:27]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture consisting of the ester (29.0 g, 0.0765 mol) of Step A, methanol (800 mL), water (50 mL) and potassium hydroxide (16.0 g, 0.29 mol) is refluxed for 4 hours. The reaction mixture is cooled to room temperature, concentrated and diluted with water (500 mL). The aqueous layer is washed with ether (2×200 mL) and made acidic with a 1:1 mixture of concentrated HCl and water to pH 2.71 is extracted with chloroform (4×300 mL) and the combined chloroform layers are washed once with water (2×300 mL), once with brine (300 mL), dried (MgSO4), filtered and concentrated to give 26.0 g of title compound, m.p. 163°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Yield: 92.1 %

Procedure:
A mixture of ethyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetate (1.33 g), a 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration to give [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl]amino}phenyl]acetic acid as colorless crystals (1.14 g, yield 91%). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 245-246° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22]([OH:24])=O)=[CH:20][CH:21]=1)=[O:16].[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22](=[O:24])[NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:39])=[CH:20][CH:21]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
Under an argon atmosphere 21.0 g (129 mmol) carbonyldiimidazol was added to a solution of 24.1 g (129 mmol) thiophene-2,5-dicarboxylic acid monomethyl ester in 600 ml THF. After 2 h at rt 26.9 g (129 mmol) (2-amino-phenyl)-carbamic acid tert-butyl ester were added and the reaction mixture was stirred for further 4 h at rt. The solvent was evaporated and the residue dissolved in 500 ml ethyl acetate. The organic phase was washed three times with 100 ml saturated aqueous NaHCO3 solution, twice with 80 ml water and was dried over sodium sulfate. The solvent was removed down to 80 ml when crystallization started. After 12 h the crystalls were filtered off and washed with little ice-cold t-butyl methyl ether and cold heptane. Drying under high vacuum yielded 38.9 g (103.4 mmol) 5-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-thiophene-2-carboxylic acid methyl ester, 1H-NMR (D6-DMSO) δ=1.45 (s, 9H), 3.87 (s, 3H), 7.14 (m, 1H), 7.22 (m, 1H), 7.46 (m, 1H), 7.59 (m, 1H), 7.89 (m, 1H), 7.96 (m, 1H), 8.73 (br, 1H), 10.02 (s, 1H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[CH2:9][OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=[N+]([O-])c1ccc(C2SCCCS2)c(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cc([N+](=O)[O-])ccc1C1SCCCS1
Reaction time: 1 h

Procedure:
To a solution of 3.47 g (12.8 mmol) of the Compound 3c in methylene chloride (100 mL) was added pyridinium chlorochromate (4.15 g, 19.2 mmol). The mixture was stirred for one hour, an additional pyridinium chlorochromate (2.0 g) was added, and the mixture was stirred 15 hours. Diethyl ether (200 mL) was added to the reaction mixture, and the solvent was decanted and evaporated. The residue was purified by chromatography (silica gel, chloroform) to afford the Compound 3d as light yellow crystals; m.p. 99°-101° C.; IR 1730 cm-1 (C=O); 1H NMR δ1.7-2.3 (m,2H, --CH2CH2CH2 --), 2.8-3.3 (m, 4H,--CH2CH2CH2 --), 6.13(s, 1H, --SCHS--), 7.8-8.7 (m,--3H, ArH), 10.45 (s, 1H,CHO).
Reaction SMILES: [F-].C([O:6][C:7]([NH:9][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N+:17]([CH3:20])[C:16]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:15]2=1)=[O:8])(C)(C)C.[OH-].[Na+].[O-:28][Mn](=O)(=O)=O.[K+]>C(Cl)Cl.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:15]2[C:14]3[C:19](=[C:10]([NH:9][C:7](=[O:8])[OH:6])[N:11]=[CH:12][CH:13]=3)[C:18](=[O:28])[N:17]([CH3:20])[C:16]=2[CH:21]=1
Reactant: C[n+]1cc2c(NC(=O)OC(C)(C)C)nccc2c2ccc(Cl)cc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)c2c(NC(=O)O)nccc2c2ccc(Cl)cc21
Temperature: 90 °C
Yield: 64.9 %

Procedure:
To a stirred solution of 4-((tert-butoxycarbonyl)amino)-8-chloro-6-methylbenzo[c][2,7]naphthyridin-6-ium fluoride (0.35 g, 0.65 mmol) and NaOH (0.162 g, 4.06 mmol) in a mixture of DCM (10 mL) and water (10 mL) was added KMnO4 (0.642 g, 4.06 mmol) in portions at rt and the reaction was heated to 90° C. for 1 h. The solution was diluted with water (10 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with water 50 mL, dried over sodium sulfate, and concentrated under reduced pressure to yield (8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-4-yl)carbamic acid (305 mg, 0.422 mmol, 65% yield) as a yellow solid, which carried on without further purification. LC/MS (ESI) m/e 304.1 [(M+H)+, calcd for C14H11ClN3O3 304.04]; LC/MS retention time (Method D): tR=1.01 min.
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH2:31][CH3:32])[C:22]=1[CH3:33])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:27][CH:28]=2)[N:23]([CH2:31][CH3:32])[C:22]=1[CH3:33])=[O:20]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Reactant: CCn1c(C)c(C(=O)NC)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCn1c(C)c(C(=O)NC)c2ccc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)cc21

Procedure:
This material was prepared by the reaction of 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with 1-ethyl-6-hydroxy-2-methyl-1H-indole-3-carboxylic acid methylamide 71e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CDCl3) δ 8.47 (1H, d, J=5.5 Hz), 7.75 (2H, m), 7.16 (1H, d, J=1.7 Hz), 7.01 (1H, dd, J=1.7, 8.4 Hz), 6.56 (1H, d, J=5.5 Hz), 5.91 (1H, bs), 4.59 (2H, m), 4.28 (2H, m), 4.11 (2H, m), 3.05 (3H, d, J=4.0 Hz), 2.72 (3H, s), 2.45 (2H, m), 1.33 (3H, m). LCMS (ESI+) [M+H]/z Calc'd 449, found 449.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].CN(C=O)C.C1C(=O)N([Br:26])C(=O)C1>CCOC(C)=O>[Br:26][C:5]1[C:4](=[O:12])[N:3]([CH3:13])[C:2]([Cl:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(=O)n(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A 250-mL round-bottom flask was charged with methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (10 g, 50 mmol), DMF (100 mL) and NBS (17.8 g, 100 mmol). The resulting mixture was stirred at room temperature for 8 hours and diluted with EtOAc (100 mL). The organic layer was washed with sat aq. NaHSO3 solution, water, dried (Na2SO4) and concentrated under reduced pressure yielding to desired product as a white solid (13.7 g, 97%)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][CH:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:43])([CH3:40])[CH3:39].CCN(CC)CC>CC(O)C>[C:38]([O:41][C:42](=[O:43])[NH:44][CH:45]1[CH2:46][CH2:47][CH:48]([NH:51][C:13]2[N:12]=[C:11]3[N:10]([C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=4)[C:16]3=[CH:15][N:14]=2)[CH2:49][CH2:50]1)([CH3:40])([CH3:37])[CH3:39]
Reactant: Clc1ncc2c(-c3cccc(Br)n3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3n2)CC1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
The mixture of 3-(6-bromo-pyridin-2-yl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine (from Example 34 supra) (3.8 g, 6.89 mmol), tert-butyl (1r,4r)-4-aminocyclohexylcarbamate (1.8 g, 8.40 mmol) and Et3N (1.2 mL, 8.3 mmo,) in IPA (80 mL) was stirred at 90° C. for 15 hours. The reaction was cooled to room temperature and the precipitate was collected by filtration to give {-4-[3-(6-bromo-pyridin-2-yl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as white powder. (Yield 1.5 g, 30%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH3:9])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=1)=[O:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture of {(S)-1-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (276 mg, 0.70 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at RT for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a yellow oil (193 mg, 94%). LCMS (Method C): RT 0.29 and 1.93 min [M+H]+ 293.2.