Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18]([OH:20])=O)=[N:10]2)[CH:4]=1)#[N:2].[NH2:21][C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][CH2:23][C@@H:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)[C@H](N)CO
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CO)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (50 mg, 0.188 mmol), (S)-2-amino-3-methylbutan-1-ol (19.37 mg, 0.188 mmol), and triethylamine (0.052 mL, 0.376 mmol) in DMF (2 mL) was added HATU (71.4 mg, 0.188 mmol). The mixture was stirred at 23° C. for 30 min and purified by HPLC to give the title compound (53 mg) as a white solid. LCMS m/z=352.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 1.26 (td, J=8.0, 4.9 Hz, 1H), 2.05 (oct, J=6.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.52 (t, J=5.6 Hz, 1H), 2.78-2.82 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.7, 6.4 Hz, 1H), 3.75-3.92 (m, 3H), 7.00 (d, J=7.8 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].Br[CH2:15][C:16]([NH2:18])=[O:17].C(N=P(N(C)C)(N(C)C)N(C)C)(C)(C)C.Cl>O.CN(C=O)C>[CH:12]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:15][C:16]([NH2:18])=[O:17])[CH:3]=2)[N:7]([CH3:11])[CH:6]=1)=[O:13]
Reactant: NC(=O)CBr
Reactant: Cn1cc(C=O)c2cc(O)ccc21
Agent: CN(C)P(=NC(C)(C)C)(N(C)C)N(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc(OCC(N)=O)ccc21
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
5-Hydroxy-1-methyl-1H-indole-3-carbaldehyde (I-2) (0.5 g, 2.86 mmol), 2-Bromo-acetamide (0.43 g, 3.1 mmol), and N′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethyl-phosphorimidic triamide (2.18 mL, 8.6 mmol) were dissolved into anh. DMF (3 mL) in a seal tube. The resulting solution was then sealed and heated at 120° C. (monitored by LCMS). The reaction completed after 3.5 h. The mixture was cooled to room temperature, added 20 mL of water, and 6 N HCl to pH 2-3. The mixture was then extracted with ethyl acetate (20 mL×6). The organic layers were combined, washed with brine (10 mL×2), dried over Mg2SO4, filtered and dried under reduced pressure to give the title compound as 0.5 g orange powder (crude yield: 76%, used without further purification). LCMS (2-85% ACN/H2O in 7 min): M+ 233.1 (100%); 95% purity (at 220 nM).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]#[N:12].C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[NH:12][C:16](=[O:25])[C:17]2[C:18]([CH:24]=1)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: C[C@H]1C[C@H](CO)N(CCC#N)C1
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](C)C[C@@H]3CO)cc12

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514–522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:18]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[N:9]2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−5°−0° C.) of 6-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (600 mg, 3.14 mmol, example 78) in THF (10.5 mL) is added 60% NaH (132 mg, 3.30 mmol) and is stirred for 15 min. Iodomethane (215 μL, 3.45 mmol) is added to the reaction mixture and stirred for 2 hrs. Quenched reaction with sat NH4Cl soln and diluted with EtOAc. Washed organic layer with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound as a white crystalline solid. MS (ESI) 206 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:7]=1.[CH3:37][N:38]([CH3:46])[C:39]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH3:37][N:38]([CH3:46])[C:39]1[C:44]([NH:45][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)[CH:3]=2)=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: COc1ccc(COc2cc(Br)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Reactant: CN(C)c1ncccc1N
Product: CN(C)c1ncccc1Nc1cc(O)cc(-c2cccc3[nH]ccc23)c1

Procedure:
Dimethyl-(3-nitro-pyridin-2-yl)-amine was obtained as a byproduct from the reaction of 2-chloro-3-nitro-pyridine with pent-4-en-1-ol (2 eq.) and sodium hydride (3 eq.) in DMF at 100° C. overnight. To this compound (0.122 g) in a mixture of ethyl acetate/methanol (5 mL, 1:1) was added 10% Pd on carbon (24 mg). The reaction mixture was hydrogenated at 50 psi hydrogen overnight. After filtration and removal of the solvents, dimethyl-(3-amino-pyridin-2-yl)-amine (0.100 g, 100%) was obtained. 4-[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-1-triisopropylsilanyl-1H-indole and dimethyl-(3-amino-pyridin-2-yl)-amine were coupled as described for Example 82. Deprotection as described in Example 35 gave 3-(2-dimethylamino-pyridin-3-ylamino)-5-(1H-indol-4-yl)-phenol. 1H NMR (400 MHz, CD3OD): δ 7.74 (dd, J=4.8, 1.5 Hz, 1H), 7.57 (dd, J=7.9, 1.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.22 (d, J=3.3 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 7.05 (dd, J=7.3, 0.8 Hz, 1H), 6.86-6.81 (m, 2H), 6.72 (t, J=1.7 Hz, 1H), 6.62 (d, J=3.1 Hz, 1H), 6.52-6.48 (m, 1H), 2.80 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCc2nnn(CCNS(C)(=O)=O)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 29.7 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.33 g), triethylamine (65 mg) and methanesulphonyl chloride (71 mg) in dichloromethane (15 ml) was heated under reflux for 2 hours and then evaporated. The residue was purified by chromatography on silica (6 g) using dichloromethane plus from 0 to 1% by volume of methanol as eluant. Appropriate fractions were combined and evaporated. The residual solid was recrystallized from ethyl acetate and dried to give the title compound (111 mg) as a hydrate, m.p. 245°-247° C. Found: C,46.23; H,5.02; N,13.82. C23H28Cl2N6O7S.H2O requires: C,46.26; H,5.19; N,14.08%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[NH:30][CH:31]=[CH:32][C:25]=23)=[S:21])[CH:13]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:30]1[C:26]2=[N:27][CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20](=[S:21])[NH:19][CH2:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][NH2:7])[CH:17]=[CH:16][CH:15]=3)=[C:25]2[CH:32]=[CH:31]1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(CNC(=S)NCc2ccnc3[nH]ccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)Nc1cccc(CNC(=S)NCc2ccnc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
To a solution of 27-1 (100 mg, 0.32 mmol) and Boc-glycine (68 mg, 0.39 mmol) in DCM (10 mL) was added TEA (98 mg, 0.96 mmol) and HATU (184 mg, 0.48 mmol). the mixture was stirred at rt for 16 h. The mixture then washed with saturated sodium bicarbonate solution (aq), and the organic layer was dried and evaporated. The residue was purified by column chromatography to yield tert-butyl(2-((3-((3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)thioureido)methyl)phenyl)amino)-2-oxoethyl)carbamate (120 mg, 0.26 mmol). To a solution of tert-butyl(2-((3-((3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)thioureido)methyl)phenyl)amino)-2-oxoethyl)carbamate (120 mg, 0.26 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at rt for 0.5 h. Solvent was evaporated and the residue was purified by semi-prep HPLC to yield Example 112, N-(3-((3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)thioureido)methyl)phenyl)-2-aminoacetamide (13 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[N:27]([CH2:28][CH2:29][O:30][C:31]4[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:32]=43)[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[C:32]4[CH:35]=[C:36]([S:39]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=4[O:30][CH2:29][CH2:28][N:27]3[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: CC(C)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCN(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 1-isopropylpiperazine (50 mg, 0.39 mmol) and NEt3 (90 μL, 0.65 mmol) in DCM (8 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (0.13 mmol) in DCM (8 mL) and the resulting mixture warmed to RT after 10 min then stirred for 2 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-7% 2M NH3/MeOH in DCM) affording 128 (41 mg, 65%) as a white solid. LCMS: RT 2.90 min [M+H]+ 486.3. 1H NMR (DMSO, 400 MHz): δ 8.79 (1H, d, J=2.41 Hz), 8.00 (1H, s), 7.94 (1H, d, J=0.61 Hz), 7.63 (1H, dd, J=8.62, 2.43 Hz), 7.28 (1H, d, J=8.62 Hz), 5.76-5.69 (1H, m), 4.64-4.62 (4H, m), 2.94-2.87 (4H, m), 2.62-2.61 (1H, m), 2.54-2.43 (4H, m), 1.49 (6H, d, J=6.62 Hz), 0.89 (6H, d, J=6.53 Hz)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[NH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>C1(C)C=CC=CC=1>[N:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][C:16]=1[N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: NCC1CCN(c2nc3ccccc3[nH]2)CC1

Procedure:
45 g of 4-aminomethylpiperidine are placed in 500 ml of anhydrous toluene in the presence of 55 g of potassium carbonate and of 50 g of 2-chlorobenzimidazole. The mixture is subjected to reflux overnight. Aver evaporation and crystallization of the oily residue, the expected product is obtained after washing with dichloromethane.
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:5]=1.[CH:21]1([O:26][C:27](Cl)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([O:26][C:27]([N:18]2[CH2:19][CH2:20][CH:15]([N:2]([CH3:1])[CH2:3][C:4]3[O:8][N:7]=[C:6]([C:9]4[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=4)[N:5]=3)[CH2:16][CH2:17]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(Cc1nc(-c2ccncc2)no1)C1CCNCC1
Reactant: O=C(Cl)OC1CCCC1
Product: CN(Cc1nc(-c2ccncc2)no1)C1CCN(C(=O)OC2CCCC2)CC1

Procedure:
The tert-butoxycarbonyl group of 4-[methyl(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylic acid tert-butyl ester (Example 119) was removed using the procedure described in Example 51 to afford methylpiperidin-4-yl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine: RT=0.65 min; m/z (ES+)=274.0 [M+H]+. Derivatisation of methylpiperidin-4-yl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine with cyclopentylchloroformate, using the procedure described for Example 52, afforded the title compound: RT=3.02 min; m/z (ES+)=386.0 [M+H]+.
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][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[CH2:25][OH:26].C(N(C(C)C)CC)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:22]3[CH2:23][CH2:24][NH:19][C@@H:20]([CH2:25][OH:26])[CH2:21]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: OC[C@H]1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: OC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Yield: 83.4 %

Procedure:
Dissolve 1-chloro-4-(4-fluorophenyl)phthalazine (0.1 g, 0.39 mmol), (R)-piperazin-2-ylmethanol (0.07 g, 0.58 mmol) and diisopropylethylamine (0.34 mL, 1.93 mmol) in DMSO (1 mL). Stir the reaction at 120° C. for 64 h. Purify the reaction mixture by flash silica gel chromatography (0-10% 2 M ammonia/MeOH in CH2Cl2) to yield the title compound as a brown solid (0.11 g, 84%). ES/MS m/z 339.0 (M+1).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH:37]2[CH2:43]Cl)=[CH:32][CH:31]=1>C(O)(C)C.CO>[CH3:42][N:39]1[CH2:38][C@@H:37]([CH2:43][O:10][C:7]2[CH:8]=[CH:9][C:3]3[O:2][CH2:1][O:5][C:4]=3[CH:6]=2)[C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1
Reactant: CN1CCC(c2ccc(F)cc2)C(CCl)C1
Reactant: Oc1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Yield: 75.6 %

Procedure:
Sesamol (4.32 g, 31.2 mmol) was added to a solution of tetrabutylammonium hydroxide in isopropanol/methanol (0.1N, 342 mL), and the solvents were evaporated under vacuum to dryness. The residual tetrabutylammonium salt of sesamol was dissolved in acetonitrile (40 mL) and 4-(4-fluorophenyl)-3-chloromethyl-N-methyl-piperidine (CIPMA) (7.5 g, 31.2 mmol) was added. The reaction mixture was stirred with heating at reflux for 4 hours. After cooling, the reaction mixture was evaporated to dryness in vacuum and the residue was dissolved in toluene. The toluene solution was washed with 5% aq. sodium hydroxide and then with water. After drying with sodium sulfate and evaporation of the solvent in vacuum, N-methylparoxetine (8.1 grams) was obtained with yield 76%.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH3:25])[C:21](=[O:24])[NH:22][CH:23]=2)[CH2:5][CH2:4]1.CS(O[CH2:31][CH:32]1[CH2:35][O:34][CH2:33]1)(=O)=O>CN(C=O)C>[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH3:25])[C:21](=[O:24])[N:22]([CH2:31][CH:32]3[CH2:35][O:34][CH2:33]3)[CH:23]=2)[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)OCC1COC1
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cn(CC2COC2)c1=O
Reaction time: 1 h
Yield: 24.8 %

Procedure:
Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to the title compound from Example 242, step 1 (80 mg) in anhydrous DMF (4 mL) After stirring 1 h, oxetan-3-ylmethyl methanesulfonate (173 mg, 1.04 mmol) was added and stirring continued for 18 h. EA extractive work up from 1 M HCl and preparative HPLC purification gave the title compound (24.0 mg) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 4.57 (t, J=6.4 Hz, 1H), 4.30 (d, J=7.2 Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.62-3.56 (m, 1H), 3.07 (s, 3H), 2.21 (s, 3H), 1.32-1.27 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 404.1 (M+1)+
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([NH:21][C:22]([N:11]2[C:12]3[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1000 %

Procedure:
Sodium hydride (802 mg, 20.0 mmol, 60% in oil) was suspended in N,N-dimethylformamide (40 ml); 5-nitroindole (2.50 g, 15.4 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 30 minutes. Phenyl isocyanate (2.01 ml, 1.23 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 1.5 hours. Water (80 ml) was added to the reaction mixture; the reaction mixture was stirred at room temperature for 30 minutes; and the precipitated crystals were filtered off, washed by water and diethyl ether one by one, and dried by means F of suction to yield the title compound (3.53 g, 12.3 mmol, 79.8%) as pale yellow crystals.
Reaction SMILES: O[C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[C:29]([NH2:30])=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:31][CH2:32][CH3:33])[CH:21]=1.C(O)C>CN(C)C=O>[CH2:32]([O:31][C:22]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]2[C:20]([CH:21]=1)=[N:19][C:11]1[C:2](=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([OH:13])=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]3=1)[N:30]=2)[CH3:33]
Reactant: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O
Reactant: CCOc1cc(N)c(N)cc1C(=O)OC
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ccccc2c2nc3cc(OCC)c(C(=O)OC)cc3nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 895 mg of ethyl 3-hydroxy-1,4-dihydro1,4-dioxo-2-naphthoate in 10 ml of N,N-dimethylformamide was added 620 mg of N,N'-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. To the mixture was added the crude methyl 4,5-diamino-2-ethoxybenzoate in 10 ml of N,N-dimethyl-formamide under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added 200 ml of ethanol, and then the resulting precipitate was collected by filtration and recrystallized from chloroform - ethanol to give the title compound, m.p. 270°-273° C., yield of 531 mg.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1ccccc1F)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2′-fluoro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.43 min; [M+H]+=455.1.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH3:29][C:30]1([CH3:35])[CH2:34][CH2:33][N:32]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:31]1
Reactant: CC1(C)CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C)(C)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3,3-dimethylpyrrolidine via General Procedure E to give 16.8 mg of 300 following reverse phase purification. MS (Q1) 461.2 (M)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:23]([C:20]2[CH:21]=[N:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[NH2:24])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: COc1ccc(C#N)cn1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(N)c2ccc(OC)nc2)cn1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To 5-bromo-2-methoxypyridine (1.00 g, 5.32 mmol) in THF (20 mL) at −78° C. was added n-butyllithium (3.13 mL, 7.83 mmol, 2.5 M in hexane). The reaction was aged at −78° C. for about 25 min at which point the cold bath was removed. 6-methoxypyridine-3-carbonitrile (1.00 g, 7.46 mmol) in THF (10 mL) was added and the reaction aged for about 40 min warming to rt at which point the reaction was concentrated. The residue was diluted with MeOH (20 mL) and NaBH4 (0.282 g 7.46 mmol) was added. The reaction aged about 90 min at rt. The reaction was concentrated and diluted with EtOAc and aq HCl (15 mL, 2 M). The aq portion was extracted twice with EtOAc before adding aq NaOH (20 mL, 2M). The aq portion was then extracted three times with EtOAc. The combined organic portion was concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc/hexane followed by 0-20% MeOH (containing 1.5% triethylamine)/EtOAc affording the title compound. HPLC/MS: 246 (M+1); Rt=1.61 min.