Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=NN.[CH2:18]([N:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:18]([N:24]1[C:25](=[O:30])[CH:26]2[CH:27]([C:4]2([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:3][C:2]([F:17])([F:16])[F:1])[C:28]1=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCN1C(=O)C=CC1=O
Reactant: NN=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 223.4 %

Procedure:
3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone hydrazone (Preparation 104, 150 mg, 0.6 mmol) was dissolved in dioxan (10 ml) and manganese dioxide (600 mg, 7.1 mmol) was added in one portion at room temperature. After stirring for 30 min, the reaction mixture was filtered through a pad of Arbocel™ directly into a flask containing a stirred solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 44 mg, 0.2 mmol) in dioxan (10 ml). The filter pad was washed further with dioxan (40 ml), and was also added to the reaction mixture. The resulting amber-yellow solution was stirred for 16 h at room temperature. The colourless mixture was then heated under reflux for 1 h before cooling to room temperature and concentrating in vacuo. The residue was purified by chromatography on silica gel (10 g), eluting with hexane:ether (2:1) to give the product as a white solid (178 mg, 74%).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][C:8]([OH:16])=[C:9]([C:12]=1[CH:13]([CH3:15])[CH3:14])[CH:10]=O)(=O)C.C([O:24][C:25]1[C:26]([CH:38]([CH3:40])[CH3:39])=[CH:27][C:28]([OH:37])=[C:29]([C:32]=1[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=O)(=O)C>>[C:17]([C:6]1[C:5]([OH:4])=[C:12]([CH:13]([CH3:14])[CH3:15])[C:9]2[CH2:10][C:25]([CH3:26])([CH3:32])[O:16][C:8]=2[CH:7]=1)([CH3:18])([CH3:19])[CH3:20].[C:33]([C:32]1[C:29]2[CH2:30][C:5]([CH3:6])([CH3:12])[O:37][C:28]=2[CH:27]=[C:26]([CH:38]([CH3:40])[CH3:39])[C:25]=1[OH:24])([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)(C)C
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)C
Product: CC(C)c1c(O)c(C(C)(C)C)cc2c1CC(C)(C)O2
Product: CC(C)c1cc2c(c(C(C)(C)C)c1O)CC(C)(C)O2

Procedure:
The mixture of 5-acetoxy-4-t-butyl-2-hydroxy-6-isopropylbenzaldehyde and 5-acetoxy-6-t-butyl-2-hydroxy-4-isopropylbenzaldehyde was treated in the same manner as in Examples 19-4), 5) and 6) to give 171 mg of 6-t-butyl-5-hydroxy-2,2-dimethyl-4-isopropyl-2,3-dihydrobenzofuran as a white solid and 75 mg of 4-t-butyl-5-hydroxy-2,2-dimethyl-6-isopropyl-2,3-dihydrobenzofuran as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[C@H:12]([CH2:17][NH2:18])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH:29]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:39][N:38]1[C:34]([C:30]2[CH:29]=[C:28]([NH:27][C:26]([NH:18][CH2:17][C@H:12]3[C@@H:13]([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:11]3)=[O:25])[CH:33]=[CH:32][CH:31]=2)=[N:35][N:36]=[N:37]1
Reactant: C[C@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CNC(=O)Nc1cccc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A solution of cis-1-[2-(4-fluorophenyl)ethyl]-4-methyl-piperidin-3-ylmethylamine (54 mg, 215 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (64 mg, 215 μmol) in N,N-dimethylformamide (2 mL) was treated with triethylamine (60 μL, 431 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonium hydroxide, to provide an amorphous solid (73 mg, 75%). 1H NMR (300 MHz, CDCl3) δ7.95 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.29 (m, 1H), 7.11 (m, 2H), 6.97 (t, J=9 Hz, 2H), 4.17 (s, 3H), 3.42 (m, 1H), 3.26 (m, 1H), 3.1-2.5 (m, 8H), 2.1-1.6 (m, 4H), 0.99 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 452.1 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])(O)=[O:26].[Na+]>>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]([NH2:24])=[O:26])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(C)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc(C3(C(N)=O)CCOCC3)cc2)CC1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
4-[4-(1-Isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile (50 mg, 0.152 mmol) was combined with boron trifluoride-acetic acid complex (500 μL, 3.6 mmol) and stirred at ambient temperature for 18 hours, followed by 65° C. for 3 hours. The reaction mixture was allowed to cool and then basified with saturated NaHCO3 solution (15 mL). The product was extracted with dichloromethane (2×35 mL). The combined organic extracts were dried using Na2SO4 filtered and concentrated in vacuo. The compound was purified by column chromatography on silica gel (15 g), eluting with dichloromethane:methanol:ammonia, (96:4:0.4) to dichloromethane:methanol:ammonia, (90:10:1) to give the title compound as a white solid (22 mg, 42%). 1H NMR (400 MHz, CD3OD) δ7.3 (d, 2H), 6.9 (d, 2H), 4.4 (m, 1H), 3.8 (m, 2H), 3.65 (m, 2H), 2.78-2.85 (m, 3H), 2.5 (m, 2H), 2.4 (d, 2H), 1.95-2.08 (m, 4H), 1.8 (m, 2H), 1.1 (d, 6H)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][O:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][O:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH:28]/[C:13](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: COc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1N/C(=C1\C(=O)Nc2ccccc21)c1ccccc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 2-methoxyaniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@H:26]([CH2:45][C:46]3[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[C:49]([NH2:56])=[C:48]([Cl:57])[CH:47]=3)[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=[O:43])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:58]=[CH:59][CH:60]=[CH:61][C:12]=2[NH:11]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@H:26]([CH2:45][C:46]3[CH:51]=[C:50]([C:52]([F:53])([F:55])[F:54])[C:49]([NH2:56])=[C:48]([Cl:57])[CH:47]=3)[C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:41][C:42]([O:44][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:43])[CH2:37][CH2:36]4)[CH2:33][CH2:34]3)=[O:28])=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:58]=[CH:59][CH:60]=[CH:61][C:12]=2[NH:11]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc1C(F)(F)F
Reactant: COCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 μL (0.11 mmol) 2-(2-methoxy-ethoxy)-ethanol were added to a mixture of 75 mg (0.10 mmol) of (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 4.1), 35 mg (0.11 mmol) TBTU and 28 μL (0.20 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred for 1 h at RT. This was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O[C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(O[C@H]2CCOC2)cc1
Temperature: 85 °C
Yield: 29.9 %

Procedure:
A mixture of 4-bromophenol (1.8 g, 10.5 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.3 g, 9.5 mmole) and K2CO3 (4.0 g, 29 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, eluting with 5% ethyl acetate in hexane) to give the title compound (690 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([SH:8])[CH2:4][CH2:3]1.CN(C)C=O.[H-].[Na+].[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19](F)[CH:18]=1>O>[F:16][C:17]1[CH:18]=[C:19]([S:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1
Reactant: CN1CCC(S)CC1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Sc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 10.7 %

Procedure:
Combine 1-methyl-piperidine-4-thiol (1.4 g, 10.67 mmol) and N,N-dimethylformamide (10 mL) and cool to 0° C. Add 95% sodium hydride (0.28 g, 11.20 mmol), warm to ambient temperature and stir. After 40 min., add 1,3-difluoro-5-nitro-benzene (1.21 mL, 10.67 mmol), stir and heat at 65° C. After 3 hr., cool to ambient temperature and add water (50 mL). Extract with ethyl acetate (3×50 mL), wash combined organic layers with water (3×50 mL), aqueous NaCl solution (50 mL), dry organic layer over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain the title compound (0.31 g, 11%). Mass spectrum (electrospray): m/z=271.1 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Br:31][C:32]1[C:40]2[C:39](Cl)=[N:38][CH:37]=[N:36][C:35]=2[NH:34][CH:33]=1>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:39]2[C:40]3[C:32]([Br:31])=[CH:33][NH:34][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:13][CH2:12]1
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(Br)c23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 10.8 %

Procedure:
DIPEA (0.670 mL, 3.85 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (400 mg, 1.28 mmol) and 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 50) (298 mg, 1.28 mmol) in butan-1-ol (6 mL). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and triturated with diethyl ether to afford (S)-4-amino-1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (70.0 mg, 10.8%) as a white solid.
Reaction SMILES: Cl.[SH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)(=O)C>[C:22]1([C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:2][C:3]2[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCc1ncccc1S
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1ncccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
Into a 3 L round bottom flask equipped with mechanical stirrer and nitrogen purge was charged 3-mercapto-2-hydroxymethylpyridine hydrochloride (25.0 g, 0.141 mol, 1 eq.) followed by DMF (1.2 L) and to the cloudy suspension was charged finely powdered potassium carbonate (58.5 g, 0.423 mol, 3.0 eq.). To the resulting solution was charged triphenylmethylchloride (38.1 g, 0.137 mol, 0.97 eq) and the reactions mixture was allowed to stir at room temperature for three hours until TLC analysis showed reaction completion (ethyl acetate-hexanes). The DMF solution was poured into 3 L of 4:1 water/ethyl acetate. The aqueous layer was separated and extracted an additional time with ethyl acetate (200 mL). The organics were combined and hexane (150 mL) was added. The organic layer was washed with water (2×200 mL) then brine (2×200 mL). The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to give 48.63 g of the title compound as a brown oil which was taken directly on to the next reaction. 1H NMR (CDCl3) δ 5.05 (s, 2H); 7.1-7.4 (m, 16H); 8.20 (d, 1H); 8.58 (d, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:22][C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24]>>[NH:21]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH2:22])=[O:24])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][N:19]=[N:20]1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: NC(=O)c1cccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)c1
Yield: 12.7 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 3-aminocarbonylphenylboronic acid (10 mg, 0.06 mmol) giving 2.7 mg (13%) of the title compound. MS (ESI+) calcd for C18H14N6O3S2 426.056880, found 426.057610.
Reaction SMILES: [CH3:1][Si:2]([CH3:6])([CH3:5])[CH2:3][Cl:4].[Mg].[CH3:8][SiH:9]([CH3:11])Cl>O1CCCC1>[CH3:1][Si:2]([CH3:6])([CH3:5])[CH2:3][Cl:4].[CH3:1][Si:2]([CH2:3][SiH:9]([CH3:11])[CH3:8])([CH3:6])[CH3:5]
Reactant: C[SiH](C)Cl
Agent: C[Si](C)(C)CCl
Agent: [Mg]
Solvent: C1CCOC1
Product: C[SiH](C)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.6 %

Procedure:
The Grignard reagent of trimethylchloromethylsilane was prepared by reacting trimethylchloromethylsilane (12.3 grams, 0.1 mole) with magnesium chips (2.88 grams, 0.12 mole) in tetrahydrofuran (50 milliliters. The Grignard reagent was then added dropwise into dimethylchlorosilane (9.46 grams 0.1 mole), which was dissolved in tetrahydrofuran (50 milliliters). The mixture was stirred at room temperature overnight, quenched with hydrochloric acid solution (20 milliliters), and extracted with diethyl ether (100 milliliters). The organic layer was washed with distilled water three times and dried with anhydrous sodium sulfate. The mixture was purified by distillation at 118-119° C. to yield (trimethylsilylmethyl)dimethylsilane product (13.0 grams, 89% yield) as a clear, colorless liquid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:16]3[C@@H:17]4[C@@H:22]([C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2ncsc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 24 %

Procedure:
The title compound is prepared from benzothiazole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 24% of theory; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:19](=[O:21])[CH3:20])[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCSc2ccccc2C1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (5 g, 30.3 mmol) in dry dichloromethane (100 mL) was added triethylamine (5.06 mL, 36.3 mmol) at room temperature, followed by the dropwise addition of acetic anhydride (3.43 mL, 36.3 mmol) at 0° C. under nitrogen. The resulting solution was stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The mixture was washed with brine (50 mL×2), dried over sodium sulfate, filtered and concentrated in vacuo to afford 6.28 g of product as yellow oil, which was used for next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH3:32])=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH3:32])=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1)[CH3:14]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(C)cc(=O)oc4c3)c2cc1OCC
Temperature: 100 °C
Yield: 71.8 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 330 mg (1.88 mM) of 7-Amino-4-methyl-coumarin in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 431 mg of 6,7-Diethoxy-4-(4-methyl-2-oxo-2H-chromen-7-ylamino)-quinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 416.0, mp=282-284° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:16][I:17]>C(#N)C>[I-:17].[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N+:12]([CH3:16])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CI
Reactant: CN(C)c1ccc(-c2ccncc2)cc1
Solvent: CC#N
Product: CN(C)c1ccc(-c2cc[n+](C)cc2)cc1
Product: [I-]
Temperature: 25 °C

Procedure:
N,N-dimethyl-4-(pyridine-4-yl)aniline (0.15 g, 7.6 mmols) was dissolved in acetonitrile (50 ml) and methyl iodide (4 ml) was added. The mixture was heated at reflux for 4 hrs then cooled to ambient temperature. IDT307 (0.17 g, 5 mmols) crystallized upon standing and was removed via filtration. 1H NMR (DMSO-d6) δ 3.40 (s, 6H), 4.25 (s, 3H), 6.92 (d, 2H), 8.06 (d, 2H), 8.38 (d, 2H), 8.80 (d, 2H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cc1cccc(CC(=O)O)c1C
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2,3-dimethylphenyl)acetic acid (33.9 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 2.12 (s, 3H), 2.27 (s, 3H), 3.24-3.31 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 4.24-4.32 (m, 2H), 7.03 (d, J=6.82 Hz, 2H), 7.05-7.09 (m, 1H), 7.43 (d, J=8.34 Hz, 1H), 7.52 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]1([N:19]2[CH:24]=[C:23]([CH:25]=[CH2:26])[CH:22]=[CH:21][C:20]2=[O:27])[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:23]3[CH:22]=[CH:21][C:20](=[O:27])[N:19]([CH:16]4[CH2:17][CH2:18]4)[CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(=O)n(C2CC2)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)n(C3CC3)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-cyclopropyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.