Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.C1C[O:18][CH2:17]C1>>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([CH:17]=[O:18])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: C1CCOC1
Agent: [CH2-]CCC
Agent: [Li+]
Product: COc1ccc(C=O)cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
N-butyllithium, 1.6 M solution in hexanes (1.05 eq, 7.0 ml) was added dropwise to a solution of 5-bromo-2-methoxy-pyridine (2 g, 10.63 mmol) in THF, Acros dry (25 ml) under argon atmosphere at −78° C. After complete addition the mixture was stirred for another 90 minutes at −78° C. at which time DMF, acros dry (2 eq, 1.65 ml) was added dropwise. The mixture was then stirred at −78° C. for another 90 minutes. The mixture was then warmed-up to room temperature and poured into 150 ml of NaHCO3 saturated water solution. The organics were extracted with 3×70 ml of diethyl ether. The gathered ether layers were dried over Na2SO4 the solvent was evaporated and the obtained crude was purified by chromatography on BIOTAGE SP1 purification device using 25 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 1-10% of EtOAc in 20 column volumes) Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 6-methoxy-pyridine-3-carbaldehyde (1.04 g, yield=71.2%, purity=95%) in form of white crystals. MS: [M+H]+=138.09 1H NMR (300 MHz; CDCl3) δ/ppm 4.04 (s, 3H), 6.85 (d, J=8.70 Hz, 1H), 8.07 (dd, J=8.70 Hz, J=2.34 Hz, 1H), 8.64 (d, J=2.34 Hz, 1H), 9.96 (s, 1H)
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[OH:8][CH2:9][CH:10]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[H+].O>ClCCl>[CH3:3][O:8][CH2:9][CH:10]([C:15]1[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: O
Product: COCC(C(=O)OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
(Diazomethyl)trimethylsilane (1.6 mL, 3.2 mmol) was added dropwise to a stirred, cooled (0° C.) mixture of (RS)-methyl α-(hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate (Description 7, 1.0 g, 3.2 mmol) and aqueous fluoroboric acid (48%, 585 mg, 3.2 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 20 minutes. Further (diazomethyl)trimethylsilane (0.8 mL, 1.6 mmol) was added and the mixture was stirred at room temperature for 20 minutes. Further (diazomethyl)trimethylsilane (0.4 mL, 0.8 mmol)) was added and the mixture was stirred at room temperature for 20 minutes. Further (diazomethyl)trimethylsilane (0.4 mL, 0.8 mmol)) was added and the mixture was stirred at room temperature for 30 minutes, poured into water (40 mL) and extracted with dichloromethane (2×40 mL). The combined organic fractions were dried (MgSO4), the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10), to give the title compound as a colorless oil (834 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 3.36 (3H, s), 3.69–3.73 (1H, m), 3.74 (3H, s), 3.92–3.96 (1H, m), 3.99–4.03 (1H, m), and 7.80–7.81 (3H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:34]1([N:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)N)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([N:40]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:32])[CH:11]=[CH:10][CH:9]=4)[CH2:13][CH2:14]3)=[C:24]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl}propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 584.3 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)=[O:13])[CH:10]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.[N+](C1C=CC([C:53]2[CH:61]=[CH:60][CH:59]=[CH:58][C:54]=2[C:55]([O-])=[O:56])=CC=1)([O-])=O>C(Cl)Cl>[C:55]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)=[O:13])[CH:10]=1)=[NH:3])(=[O:56])[C:54]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:53]=1
Reactant: Cc1cc(NC(=O)Cc2cc(C(=N)N)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1
Reactant: O=C([O-])c1ccccc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)Cc2cc(C(=N)NC(=O)c3ccccc3)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1

Procedure:
350 mg (0.69 mmol) of 2-(5-carbamimidoyl-2-benzyloxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetamide-hydrochloride are suspended in 40 ml of methylene chloride and combined with 1.0 ml of triethylamine and 300 mg (1.3 mmol) of 4-nitrophenylbenzoate. The reaction mixture is refluxed for 4 hours. After the addition of 100 ml of saline solution the aqueous phase is extracted 3× with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Br:15][C:16]1[CH:17]=[C:18]([C:28](O)=O)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([C:28]2[O:12][C:11](=[O:13])[C:10]3[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]4[CH:6]=[N:7][NH:8][C:9]4=3)[N:1]=2)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 700 mg (3.66 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 26 mL of anhydrous acetonitrile is added 1.11 g (3.66 mmol) of 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid followed by 1.3 mL (16.2 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 1.0 mL (12.9 mmol) of methanesulfonyl chloride is added drop wise. The mixture is stirred at ambient temperature for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. The pale yellowish product obtained (1.6 g) is engaged in the next step; LC/MS:459/461 (M+H)+.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=O.[Na+].C([O-])(=O)C.[NH4+:11].[C:12]1([CH:20]=[CH:19][CH:18]=[C:16]([OH:17])[C:14]=1[OH:15])[OH:13]>O>[OH:13][C:12]1[C:14]([OH:15])=[C:16]([OH:17])[CH:18]=[CH:19][C:20]=1[NH:11][CH2:2][C:1]([OH:5])=[O:4]
Reactant: Oc1cccc(O)c1O
Reactant: [NH4+]
Reactant: O=CC(=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CNc1ccc(O)c(O)c1O
Yield: 20.6 %

Procedure:
36.9 g of sodium glyoxylate, 75 g of ammonium acetate, 81.5 g of pyrogallol and 130 ml of water are treated in the same manner as described in Example 1. 13.3 g of DL-(2,3,4-trihydroxyphenyl)glycine are thereby obtained as crystals. Yield: 20.6% M.p. 198°-203° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27](OC)=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24](C)[N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[C:54]1(C)C=CC=CC=1>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:54])=[C:26]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:34][CH2:35]2)[N:25]=[C:24]([O:50][CH3:49])[N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: COc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)nc(C)nc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)O)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1

Procedure:
280 mg (0.443 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{5-methoxy-2-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in 15 ml of dichloromethane with 3 ml of trifluoroacetic acid is stirred at ambient temperature for 18 hours. Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane then poured into diisopropyl ether. 210 mg of expected product is obtained by filtration in the form of a white solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:19][C:20]1[C:27]([O:28][CH3:29])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[Br:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:31](#[N:35])[CH2:32][C:33]#[N:34].N1CCCCC1>C(O)C.O>[NH2:35][C:31]1[O:11][C:1]2[C:2]([CH:24]([C:23]3[CH:26]=[C:27]([O:28][CH3:29])[C:20]([O:19][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:21]([Br:30])[CH:22]=3)[C:32]=1[C:33]#[N:34])=[CH:3][CH:4]=[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=21
Reactant: COc1cc(C=O)cc(Br)c1OCc1ccccc1
Reactant: N#CCC#N
Reactant: Oc1cccc2ccccc12
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OCc1ccccc1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
1-Naphthol (2.16 g, 15 mmol), 4-benzyloxy-3-bromo-5-methoxy-benzaldehyde (4 g, 12.5 mmol) and malononitrile (825 mg, 12.5 mmol) were taken in 30 ml ethanol at room temperature, charged with piperidine (200 μl) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was then cooled down to room temperature, diluted with 60 ml water and stirred for about 2 h at room temperature. Thus formed precipitates were collected by filtration, washed with 1:1 mixture of ethanol/water and dried under high vacuum yielding pure solids of the title compound (6.0 g, 11.7 mmol, 93.5%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7]([NH2:9])=[O:8].[CH2:15]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:21])[CH3:16]
Reactant: CCCc1nn(CC)c(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCCc1nn(CC)c(C(N)=O)c1NC(=O)c1ccccc1OCC

Procedure:
The title amide was prepared from 4-amino-1-ethyl-3-n-propylpyrazole-5-carboxamide and 2-ethoxybenzoyl chloride, following the procedure described in Example 6, and was obtained as a colourless solid (73%), m.p. 139°-141° C. Found: C,63.03; H,7.15; N,16.50. C18H24N4O3 requires C,62.77; H,7.02; N,16.27%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[C:15]([CH3:16])=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:17])=[O:5].C([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH:8]1[C:28]2[CH2:19][C:18]3[CH:3]=[CH:2][CH:21]=[CH:20][C:31]=3[CH2:30][N:26]([C:11]([C:10]3[CH:14]=[C:15]([CH3:16])[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=4[Cl:1])=[C:8]([CH3:17])[CH:9]=3)=[O:13])[C:27]=2[CH:29]=[CH:15][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.8 %

Procedure:
A mixture of 1.69 g of 4-[(2,4-dichlorobenzoyl)amino]-3,5-dimethylbenzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath under argon for 1 hour. The volatiles are evaporated and the residue evaporated in vacuo from toluene to give a residue. A solution of the residue in 25 ml of methylene chloride is treated with 0.75 g of N,N-diisopropylethylamine and 0.98 g of 10,11-dihydro-5H-dibenz[b,e]azepine is stirred at room temperature for 18 hours. The reaction mixture is washed with saturated NaHCO3, dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a glass which is dissolved in methylene chloride dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated to give 1.89 g of the desired product as an amorphorous solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[C:25]4[CH:26]=[CH:27][CH2:28][CH2:29][C:30]=4[C:31](=[O:32])[C:16]=23)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[C:9]1([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[C:25]4[C:30]([C:31]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)([OH:32])[C:16]=23)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1C2=C(C=CCC2)c2nc3ccccc3c(-c3ccccc3)c21
Solvent: C1CCOC1
Product: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Yield: 90 %

Procedure:
After dripping 1M phenylmagnesium bromide (20 ml, 20.0 mmol) into the starting material 10-phenyl-1H-indeno[1,2-b]quinolin-11-one (3.07 g, 10.0 mmol) which is dissolved in pure tetrahydrofuran, the mixed solution undergoes reaction for 24 hours at room temperature. Then, the reaction is terminated by adding ammonium chloride solution therein. Finally, 3.47 g of 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol is obtained by filtering the mixed solution to remove precipitates. The percentage yield is 90.0%. 10-diphenyl-11H-indeno[1,2-b]quinolin-11-ol obtained here can be also used as starting materials to produce other 6H-indeno[2,1-b]quinoline derivatives.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([N:37]4[CH2:38][CH2:43][CH2:42][CH2:41]4)=[O:24])[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(C(=O)O)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(C(=O)N4CCCC4)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing 55 mg (0.12 mmol) of the product from Step C with 24 mg (0.18 mmol) of 1-hydroxybenzotriazole, 0.015 mL (0.18 mmol) of pyrrolidine, and 0.031 mL (0.18 mmol) of N,N-diisopropylethylamine in 1.0 mL of DMF was added 35 mg (0.18 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. The resulting mixture was stirred at ambient temperature for 16 h, then concentrated and purified directly by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 5% to 80% acetonitrile/water with 0.1% TFA) to give the title compound. LC/MS 515.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([NH:17][CH3:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)(=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([N:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH3:18])=[CH:15][CH:14]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(c1ccc(Cl)cc1)c1ccnc2ccccc12
Yield: 97 %

Procedure:
A solution of 4-chloroquinoline (5 mmol) and of 4-chloro-N-methylaniline (10 mmol) in glacial acetic acid (15 ml) was heated with reflux for 3 h under a stream of argon. After cooling, the solution was basified with a 10% NaOH solution until pH=10 and the resulting suspension was concentrated in a rotary evaporator and purified by means of flash chromatography (9:1, CH2Cl2:MeOH) to give the target molecule as a yellowish syrup (97%). 1H-NMR (400 MHz, CDCl3): δ 8.10 (d, J=8.5, 1H, H-2quin) 7.70 (d, J=8.5, 1H, H-5quin); 7.65 (t, J=7.9, 1H, H-7quin) 7.38 (t, J=8.5, 1H, H-6quin); 7.35 (d, J=7.9, 1H, H-8quin) 7.17 (d, J=8.9, 2H, H-3,5anil); 7.14 (d, J=8.5, 1H, H-3quin) 6.76 (d, J=8.9, 2H, H-2,6anil); 3.45 (s, 6H, Me). 13C-NMR (100 MHz, CDCl3): δ 153.37 (C-4quin); 151.16 (C-2quin); 150.01 (C-1anil) 148.17 (C-8aquin); 135.02 (C-4anil); 130.07 (C-7quin); 129.52 (C-6quin); 129.29 (C-3,5anil); 126.26 (C-4aquin); 126.07 (C-5quin); 124.40 (C-8quin); 119.79 (C-2,6anil); 115.08 (C-3quin); 41.75 (Me). HRMS (m/z): Calculated for C16H13N2Cl [(M+H)]+ 269.0845. Found: 269.0845. Analysis for C16H13N2Cl. Calculated: C, 71.51; H, 4.88; N, 10.42%. Found: C, 71.60; H, 4.71; N, 10.33%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+:10].[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1.[CH3:21][CH2:22][OH:23]>C1COCC1.C(#N)C>[C:14]([C:13]1[CH:12]=[CH:21][C:22](=[O:23])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:20])=[CH:12][CH:13]=2)[C:18]=1[S-:19])#[N:17].[Na+:10]
Reactant: Cc1ccc(N=C=S)cc1
Reactant: CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(-n2c([S-])c(C#N)ccc2=O)cc1
Temperature: 25 °C
Yield: 39 %

Procedure:
Sodium bis(trimethylsilyl)amide (36.8 mL, 1.0M in THF, 36.8 mmol) was added slowly to a solution of 4-tolyl isothiocyanate (2.5 g, 16.75 mmol) in THF (30 mL) and acetonitrile (5 mL) at −78° C. The mixture was warmed to r.t. over 1 h. N,N-Dimethyluracil (2.35 g, 16.75 mmol) and EtOH (20 mL) were added and the mixture heated at reflux for 4 h. Volatiles were removed in vacuo and the residue was dissolved in EtOH (6 mL). Et2O (˜60 mL) was added slowly to produce a fine, off-white solid. The suspension was cooled to 0° C. and the solid filtered off, washed with Et2O and dried to give the title compound as an off-white solid (1.7 g, 39%). δH (DMSO-d6) 7.15-7.12 (3H, m), 6.80-6.77 (2H, m), 5.60 (1H, d, J 9.1 Hz), 2.30 (3H, s).
Reaction SMILES: [Br:1][CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16](=[O:26])[O:17][C@@H:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[CH:11][CH:10]=1>CCOC(C)=O>[Br-:1].[CH2:34]([O:33][C:31]([C:30]1[CH:29]=[C:28]([NH:27][CH:15]([C:12]2[CH:13]=[N:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[C:16]([O:17][C@@H:18]2[CH:23]3[CH2:24][CH2:25][N+:20]([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])([CH2:21][CH2:22]3)[CH2:19]2)=[O:26])[CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:35]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(CC=C(C)C)CCC2CC3)c2ccc(OC)nc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
1-Bromo-3-methylbut-2-ene (16.9 mg, 0.11 mmol) was added to a solution of ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (C65) (50 mg, 0.11 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with Et2O, filtered and dried. The product was purified by flash-chromatography (DCM/MeOH=97/3 to 9/1) to obtain (3R)-3-(2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-(3-methylbut-2-enyl)-1-azoniabicyclo[2.2.2]octane bromide (56 mg, 84% yield).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].O.[Cl-].[Na+]>N1C=CC=CC=1>[C:13]([O:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]#[N:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc2c1CCC2O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCc2c(C#N)cccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
3.89 g of (RS) 1-hydroxy-4-indanecarbonitrile in 39 ml of pyridine is cooled to 0° C., 3.45 ml of acetic anhydride is added drop by drop, and the whole is agitated for 16 hours at 20° C. The reaction mixture is poured into 300 ml of water containing sodium chloride and extracted with isopropyl ether; the ethereal phase is washed with 2N hydrochloric acid and then with water until pH 7 is obtained. The ethereal phase is dried and brought to dryness, and the residue is taken up in 1,2-dichloroethane, and again concentrated to dryness under reduced pressure. The residue is taken up in 40 ml of hexane, agitated for one hour, filtered, and 4.46 g of expected product is recovered. M.p.=65° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH2:18]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[N:23]=[CH:22]1)[C:19]#[CH:20].[CH3:31][CH:32](O)[CH3:33]>>[C:18]1([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([NH:30][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH:33]=[CH:32][CH:31]=[CH:20][CH:19]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: CC(C)O
Reactant: C#CCn1cnc2cc(N)ccc21
Product: c1ccc(-c2nnc(Nc3ccc4c(c3)ncn4-c3ccccc3)c3ccccc23)cc1
Yield: 99 %

Procedure:
A solution of 1-chloro-4-phenylphthalazine (81 mg, 0.34 mmol) and 1-(prop-2-ynyl)-5-aminobenzimidazole (3) (36 mg, 0.21 mmol) in i-PrOH (6 mL) is stirred at 95° C. under argon for 2 h and then concentrated. The residue is diluted with sat. NaHCO3 (15 mL) and extracted with CHCl3 (60 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (1% to 10% methanol/ethyl acetate) to give 78 mg (99%) of 5 (BI-3007) as a yellow solid, mp 227-229° C. IR 3304, 2965, 1495, 1401 cm−1; NMR (DMSO-d6) δ 3.54 (t, J=2.4 Hz, 1H, CH≡CCH2), 4.83 (bs, 2H, NH2), 5.24 (d, J=2.4 Hz, 2H, CH≡CCH2), 7.52-7.62 (m, 3H, PhH), 7.64 (d, J=8.7 Hz, 1H, 7-BenzimidH), 7.65-7.71 (m, 2H, PhH), 7.79 (dd, J=8.7, 1.8 Hz, 1H, 6-BenzimidH), 7.89 (d, J=8.1 Hz, 1H, 5-PhthH), 7.91-7.98 (m, 1H, 6-PhthH), 7.99-8.08 (m, 1H, 7-PhthH), 8.25 (s, 1H, 2-BenzimidH), 8.34 (d, J=1.8 Hz, 4-BenzimidH), 8.72 (d, J=8.1 Hz, 8-PhthH), 9.32 ppm (s, 1H, NH).