Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH2:4][CH2:3]1.[C:21]([O:25][C:26]1[C:27]([CH:32]=O)=[N:28][CH:29]=[CH:30][N:31]=1)([CH3:24])([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[C:21]([O:25][C:26]1[C:27]([CH2:32][N:2]2[CH2:3][CH2:4][CH:5]([C:8](=[O:20])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:18])([F:19])[F:17])[CH2:6][CH2:7]2)=[N:28][CH:29]=[CH:30][N:31]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: O=C(Cc1ccccc1C(F)(F)F)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 88 %

Procedure:
After suspending 200 mg of 1-(piperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanone hydrochloride in 2 ml of dichloromethane, a solution of 140 mg of 3-tert-butoxypyrazine-2-carboxaldehyde in dichloromethane (2 ml) and 207 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (249 mg, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[H-].[Na+].CI.[C:25](OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:25])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C

Procedure:
2-(5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol 68 (175 mg) was cooled in DMF to 0° C. and then NaH was added at once. The reaction was allowed to warm to room temperature and stirred several minutes before addition of methyl iodide. Reaction was stirred several hours and monitored by LC-MS until complete. Ethyl acetate was added and the solution was extracted with saturated bicarbonate solution. Organic was collected and dried, filtered and concentrated to get crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].CC(=CC)C.[O-:23]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH3:2][CH2:1][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([OH:23])=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of 0.104 g (0.413 mmol) of 6-Chloro-3-formyl-1H-indole-2-carboxylic acid ethyl ester in a mixture of tert-butanol (10 ml) and H2O (5 ml), was added 2-methyl-2-butene (2 ml) followed by a solution of NaClO2 (0.344 g, 3.80 mmol) and NaH2PO4 (0.399 g, 2.90 mmol) in water (2 ml). The mixture was stirred overnight at RT. The organic solvents were removed, and then the aqueous solution diluted with water, and washed twice with hexane. The ph of the aqueous phase was adjusted to 3 by addition of aq. HCl 1N, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 15 mg (14%) of 6-chloro-1H-indole-2,3-dicarboxylic acid 2-ethyl ester as alight yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=3[CH:38]=2)[C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1([NH2:48])[CH2:47][CH2:46]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34]([NH:35][CH3:36])=[O:37])[C:23]=3[CH:38]=2)[CH:15]=[C:11]([C:12](=[O:13])[NH:48][C:45]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH2:47][CH2:46]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(OCc4ccccc4)c3C)cc12
Reactant: NC1(c2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)cc(OCc4ccccc4)c3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.40 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.064 g, 0.47 mmol, 1.2 eq) (60% purity), HOBT (0.68 g, 0.012 mmol, 1.7 eq), EDC.HCl (0.064 g, 0.72 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.26 g, 2.0 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.17 g (70%). 1H NMR (400 MHz, DMSO-d6): δ 1.26-1.27 (m, 2H), 1.54-1.56 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (s, 3H), 5.26 (s, 2H) 7.13-7.15 (q, 1H, J=4.4 Hz), 7.30-7.43 (m, 6H), 7.58 (d, 4H), 7.65-7.69 (t, 2H, J=3.9 Hz), 7.74-7.79 (d, 1H, J=8.0 Hz), 7.97-8.01 (m, 2H), 8.43-8.48 (dd, 2H, J=4.89 Hz), 9.186 (s, 1H). LCMS: (ES+) m/z=626 (M+H) Ascentis Express C18 (5.0×2.1-2.7 μm). Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH. Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH. Flow: 5 ml/Min.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].Cl[CH2:14][C:15]1[N:16]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:27])[C:18]=2[N:28]=1.O>CN(C=O)C>[OH:33][C:30]([CH3:32])([CH3:31])[CH2:29][N:16]1[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:27])[C:18]=2[N:28]=[C:15]1[CH2:14][N:10]([O:11][CH3:12])[CH3:9]
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 17 h
Yield: 16.3 %

Procedure:
Triethylamine (0.747 g, 1.03 mL, 7.38 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.480 g, 4.92 mmol) were added to a stirring suspension of 2-chloromethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.750 g, 2.46 mmol) in DMF (5 mL). The resulting suspension was heated to 50° C. and stirred for 17 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). A solid was removed by filtration and discarded. The filtrate was extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 5-20% methanol in dichloromethane). The resulting oil was crystallized from dichloromethane and isolated by filtration to yield 132 mg of 1-(2-Hydroxy-2-methylpropyl)-2-{[methoxy(methyl)amino]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 220-222° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].C(N(CC)CC)C.[CH3:25][N:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:29][C@@H:28]([NH:43][C:44](OC2C=CC([N+]([O-])=O)=CC=2)=[O:45])[C:27]1=[O:56].Cl>CN(C=O)C.C(O)C.[Pd].O>[CH3:25][N:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:29][C@@H:28]([NH:43][C:44]([NH:1][C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=2)[C:5]([OH:7])=[O:6])=[O:45])[C:27]1=[O:56]
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)O)c2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To benzyl m-aminobenzoate (0.25 g, 1.10 mmole) in DMF (17 ml) was added triethylamine (0.23 ml) followed by a solution of (R)-1,3-dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (0.469 g, 1.09 mmole) in DMF (23 ml) containing triethylamine (0.23 ml). The mixture was stirred at room temperature for one hour, then treated with water, made acidic with 1N HCl, and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 500 ml each of 5%, 6%, 7%, 9%, 10%, and 12% ether in CH2Cl2. The product fractions were combined and evaporated to dryness in vacuo. A portion of the residue (81.2 mg, 0.086 mmole) was dissolved in ethanol (70 ml) and hydrogenated over palladium/charcoal (20 mg) at 50 psi of H2. The mixture wag filtered and evaporated to dryness in vacuo to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[O:32][C:33]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[O:36]1[CH:37]=[CH:38][CH:39]=[C:35]1[C:31]1[O:32][C:33]([CH3:34])=[C:29]([CH2:28][O:1][C:2]2[CH:26]=[CH:25][C:5]([CH2:6][N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]3)=[CH:4][CH:3]=2)[N:30]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.01 g), 4-chloromethyl-2-(2-furyl)-5-methyloxazole (0.75 g), potassium carbonate (0.63 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (5 ml) and ethanol (10 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (1.02 g, yield: 73%). This was recrystallized from ethyl acetate-hexane. Melting point: 86–87° C.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH3:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1.O>CS(C)=O.CS(C)=O.O1CCCC1.O1CCCC1>[CH3:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]2[O:15][CH2:2]2)[N:13]=1
Reactant: C[S+](C)C
Reactant: Cc1nc(C=O)cs1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(C2CO2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.2 g (0.048 mol) of Trimethylsulphonium iodide are dissolved in 42 ml of dimethyl sulphoxide and added dropwise to a stirred solution, which is maintained at 0° C., of 1.14 g of sodium hydride in 50 ml of dimethyl sulphoxide/tetrahydrofuran (1:1). After 60 minutes, a solution of 6.1 g of 2-methyl-4-formylthiazole in 25 ml of tetrahydrofuran is added dropwise at 0° C., and the mixture is stirred at room temperature for 3 hours. It is then cooled to 0° C., 9.6 ml of water are added dropwise, and the mixture is extracted with ether. The ethereal phase is extracted by shaking 2× with water, dried and concentrated. The resulting oil is purified on a silica gel column using toluene/ethyl acetate (65:35) as eluant.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([OH:34])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:43][CH2:44][Cl:45].[OH-].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:43][CH2:44][Cl:45])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCCl)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A solution of 100 mg of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)indazole-1-carboxylic acid tert-butyl ester and 132 μl of 1-bromo-2-chloroethane in 5 ml of dichloromethane is mixed with an aqueous solution of 72 mg of tetrabutylammonium bromide and of 270 μl of 2N sodium hydroxide in 5 ml of distilled water. The reaction mixture is stirred vigorously at 20° C. for 6 hours. After separation by settling out and washing with water (4×5 ml), the organic extracts are combined, dried over magnesium sulfate and then evaporated under reduced pressure. The crude compound obtained is purified by preparative LC/MS. The fractions containing the expected compound are combined and evaporated under reduced pressure to obtain 18.1 mg of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-chloroethoxy)-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester, which is characterized as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([SH:11])[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[S:22](Br)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CC(C)(C)c1cc2nc(N)sc2cc1S
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc3sc(N)nc3cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to General Method 15 using 2-amino-5-tert-butyl-benzothiazole-6-thiol (7.0 g, 29 mmol), pyridine (2.3 g, 29 mmol), tosyl bromide (6.9 g, 29 mmol), carbon tetrachloride (100 mL), and EtOAc (100 mL). The crude reaction mixture was purified by flash chromatography (5% EtOAc in hexanes to 50% EtOAc in hexanes as eluents). MS(APCI): 393 (M+H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:25][CH2:24][CH2:23][CH2:22][C:17]=3[C:18]=2[C:19]([OH:21])=[O:20])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:11]3[O:20][C:19](=[O:21])[C:18]4[C:17]5[CH2:22][CH2:23][CH2:24][CH2:25][C:16]=5[S:15][C:14]=4[N:13]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1sc2c(c1C(=O)O)CCCC2)c1cccc(CN2CCOCC2)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2cccc(CN3CCOCC3)c2)nc2sc3c(c12)CCCC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A mixture of 22.2 g of 2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid and 230 mL of toluene was heated at 60° C., and 20 mL of thionyl chloride was added thereto, followed by stirring for 1 hour at 60° C. The insoluble material was collected by filtration and washed with toluene. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the material collected by filtration, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was washed with ethanol, thereby obtaining 18.9 g of 2-[3-(morpholin-4-ylmethyl)phenyl]-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-4-one.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3/[C:14](=[N:1]/[OH:3])/[C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1Cc2ccncc2Nc2ncccc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reaction time: 1.5 h
Yield: 87 %

Procedure:
A solution of sodium nitrite (3.3 g, 0.048 mol) in water (14.4 mL) was added dropwise to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (4.22 g, 0.02 mol) in acetic acid (80 mL) at room temperature. After the addition was completed, the reaction was stirred for 1.5 hours and 100 mL of water was then added. The mixture was stirred for additional 10 minutes, filtered and dried to give 4.18 g of the desired product. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.48-8.51 (m, 2H), 8.32 (d, 1H, J=5.2 Hz), 7.56 (d, 1H, J=5.6 Hz), 7.07 (dd, 1H, J1=8 Hz, J2=4.8 Hz). MS [M+H]=241.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]([OH:12])=O.[ClH:13].Cl.[NH2:15][C@@H:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[ClH:13].[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[C@@H:16]([NH:15][C:10]([C:2]1[NH:3][C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=1)=[O:12])[CH2:17]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1nc2cccnc2[nH]1
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: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@H]1CN2CCC1CC2)c1nc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (90 mg, 0.55 mmol) in DMF (4 mL) is added (R)-(+)-3-aminoquinuclidine dihydrochloride (0.11 g, 0.56 mmol), DIEA (0.25 g, 0.35 mL, 1.9 mmol) and HATU (0.21 g, 0.56 mmol). The mixture is stirred overnight at rt, diluted with CH2Cl2 (50 mL) and washed with 1 N NaOH (2×50 mL) followed by sat. aq. NaHCO3 (50 mL). The material is purified by passage through acidic ion exchange resin. The free base is taken up in 3 M HCl/MeOH (10 mL) and stirred for 1.5 hr. Isopropanol and Et2O are added and the solid is isolated by vacuum filtration to afford Example 1004 in 57% yield. MS for C14H17N5O: 272 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: c1cncc(Cn2ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
Under argon, a dimethylformamide (50 ml) solution of indole (18 g) was added into dimethylformamide (350 ml) in which 60% sodium hydride (7.9 g) was suspended, and the mixture was stirred at room temperature for 30 minutes. A dimethylformamide (100 ml) solution of 3-chloromethylpyridine hydrochloride (25 g) was added at 0° C. and the mixture stirred at room temperature for 18 hours. After the reaction, a saturated aqueous sodium hydrogencarbonate solution was added at 0° C. and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 1-(3-pyridylmethyl)indole (31.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].COCCO.[ClH:33]>C(O)(C)C>[ClH:33].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[C:8]([N:25]3[CH2:26][CH2:27][N:22]([C:20]([C:16]4[O:15][CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:23][CH2:24]3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1cc2ncn(C)c2cc1OC
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: Cl
Solvent: COCCO
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)n(C)c2cc1OC

Procedure:
3.50 g. 2-chloro. 5,6-dimethoxy-1-methyl benzimidazole [(J. Org. Chem. USSR 1 1466), (1965)] 7.00 g N-(2-furoyl) piperazine, and 25 ml 2-methoxyethanol were reacted as described in Example I. The product was converted to its hydrochloride by dissolving in isopropyl alcohol and acidifying with a solution of HCl gas in isopropyl alcohol. Yield: 3.99 g product, mp 212°-215° C decomp.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccc(F)cc3)c(=O)n12
Temperature: 100 °C
Yield: 65.5 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.32 mmol) and 4-fluorophenylboronic acid (53 mg, 0.38 mmol) in 1,4-dioxane (2 mL) was added a 1M solution of sodium carbonate in water (0.38 mL, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product (69 mg, 66%). LCMS calculated for C15H13FN5OS (M+H)+: m/z=330.1. Found: 330.0.