Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([CH2:17][CH2:18][CH:19]=O)[C:11](=[O:21])[CH:10]=[N:9]2.[NH2:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:40])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([CH2:17][CH2:18][CH2:19][NH:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]3[CH:30]=[CH:31][C:32]4[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=4[N:38]=3)[C:26](=[O:40])[CH2:25]1)[C:11](=[O:21])[CH:10]=[N:9]2
Reactant: O=CCCn1c(=O)cnc2cc(F)c(F)cc21
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1COc2ccc(N3C[C@@H](CNCCCn4c(=O)cnc5cc(F)c(F)cc54)CC3=O)nc2N1
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
Acetic acid (32 mg, 0.58 mmol) was added to a mixture of 3-(6,7-difluoro-2-oxoquinoxalin-1(2H)-yl)propanal (0.1 g, 0.45 mmol), 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Examples 54, 0.11 g, 0.45 mmol), molecular sieve (4 A, 0.1 g) and methanol (4 ml). The obtained mixture was stirred for 20 minutes, cooled on ice and sodium triacetoxyborohydride (0.11 g, 0.58 mmol) was gradually added thereto. Then, the mixture was stirred at room temperature for 4 hours, an aqueous solution of sodium hydrogen carbonate was added thereto and the mixture was extracted with ethyl acetate. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 15 mg (7%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[CH3:35][N:36]1[CH2:41]COC[CH2:37]1.C=O.CN>CCO>[Br:1][C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:37][N:36]([CH3:41])[CH2:35][N:13]([CH2:14][CH3:15])[C:12]3=[O:16])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: CN1CCOCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: C=O
Agent: CN
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (Jubilant) (3.0 g, 5.48 mmol) was suspended in EtOH (120 mL). N-methylmorpholine (3.0 mL, 27.4 mmol), aqueous formaldehyde (4.45 mL, 54.8 mmol) and methylamine solution (2 M) (13.7 mL, 27.4 mmol) were added and the reaction mixture stirred at rt for 16 h, followed by a further 4 hrs at 80° C. The reaction mixture was cooled to rt and the resulting precipitate filtered. The precipitate was washed with EtOH, Et2O and dried using a vacuum oven to afford the desired product (2.5 g, off white solid).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([CH2:19][CH2:20][PH:21](=[O:26])[CH2:22][CH2:23][C:24]#[N:25])#[N:18].CN(C)C(=O)C>O>[C:17]([CH2:19][CH2:20][P:21]([CH2:22][CH2:23][C:24]#[N:25])(=[O:26])[O:11][C:9]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)#[N:18]
Reactant: N#CCC[PH](=O)CCC#N
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1cc(OP(=O)(CCC#N)CCC#N)cc(C(C)(C)C)c1O
Yield: 40.2 %

Procedure:
2,6-Di-tert.-butyl-1,4-benzoquinone (11.0 grams; 0.05 mole) and bis-(2-cyanoethyl)phosphine oxide (8.0 grams; 0.05 mole) are dissolved in 20 mls. of N,N-dimethylacetamide and the solution is heated at reflux for 2 hours. The solution is then cooled to ambient conditions and drowned in water to precipitate a pale yellow oil which is subsequently separated, washed well with water, and extracted with diethyl ether. The ethereal extract is then stripped of diethyl ether and the residue is dried in vacuo at 50° C. to obtain 7.56 grams of a yellow oil which has an infrared absorption spectrum consistent with the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-])=O)[C:17]=1[OH:26])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=1[OH:26])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 94.9 %

Procedure:
N-[3-(tert-butoxycarbonylamino)propyl]-6-chloro-2-hydroxy-3-nitrobenzene-sulfonamide (250 mg, 0.61 mmol) was reduced with hydrogen and 10% Pd/C (100 mg) to form the desired product (220 mg, 95%). 1H NMR (MeOD-d4): δ 6.82 (m, 2H), 3.06 (t, 2H), 2.92 (t, 2H), 1.60 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1B(O)O)[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:19]=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=3[O:14][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CCOc1ccc(Cl)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-ethoxy-5-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-ethoxy-5-chloro-phenylboronic acid in a manner analogous to Example 2c (0.46 g, 66%). MS=322 (MH)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:38]1([NH:41][C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([NH:41][CH:38]4[CH2:40][CH2:39]4)=[O:50])[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CN1CCNCC1)NC1CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC2CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-cyclopropyl-2-piperazin-1-yl-acetamide (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O3 [(M+H)+] 705.3081, observed 705.308.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]#[N:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C#N)s1
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (270 mg, 0.80 mmol) produced in the same manner as in Example 35-B (ix) in tetrahydrofuran (20 mL) was added Burgess reagent (230 mg, 0.96 mmol), and the mixture was stirred for 30 min. The reaction solution was added to ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The resulting solid was collected by filtration, washed with water and dried to give the title compound (110 mg, 42%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH:10]([O:12][C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:11])C1C=CC=CC=1.C(O)(=O)C>[Pd].CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][CH:10]([CH3:11])[CH2:9][NH:8][CH3:1])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CN(C)Cc4ccccc4)c23)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CNCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12

Procedure:
Put 500 mg palladium on charcoal (10%) under argon in 100 ml methanol. Add 1.7 g (3.55 mmol) (+/−)-N-Benzyl-2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-N-methylpropane-1-amine and 2.5 ml acetic acid, and hydrogenate at RT and normal pressure. After 2 h filter with a diatomite filter and concentrate by evaporation. Dissolve the residue in water and wash twice with ethyl acetate. Discard the ethyl acetate phases. Make the aqueous phase basic with solid sodium hydrogencarbonate and extract twice with ethyl acetate. Wash the combined ethyl acetate phases once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. 900 mg (65.2% of theor.) of the target compound is obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])[CH2:27][CH2:26]3)=[N:14][CH2:15][N:16]2N2CCNCC2)=[N:11][C:10]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])[CH2:27][CH2:26]3)=[N:14][C:15]([N:11]3[CH2:12][CH2:17][NH:18][CH2:9][CH2:10]3)=[N:16]2)=[N:11][C:10]=1[S:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1CCN(C2=NCN(N3CCNCC3)c3nc(NCc4ccccc4)c(Cl)nc32)CC1
Reactant: SCc1ccccc1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3nc(NCc4ccccc4)c(SCc4ccccc4)nc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 7-benzylamino-6-chloro-4-(1-oxido-thiomorpholino)-1-piperazino-pteridine and benzylmercaptan.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](OCC)=[O:17].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][OH:17]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
14 grams (50 mmol) of ethyl 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylate was suspended in 400 ml THF, and 9.5 grams (250 mmol) lithium aluminum hydride were added slowly. The mixture was stirred at room temperature for 12 hours, cooled, 250 ml water was added and the resulting mixture was stirred overnight. The solvent was thereafter evaporated, and water (300 ml) was again added. The aqueous suspension was extracted with dichloromethane. The organic extract was evaporated, and the remaining residue was purified by column chromatography on silica gel, using a 9:1 mixture of ethylacetate and methanol as eluent, to yield 4-hydroxy-7-trifluoromethyl-3-(hydroxymethyl)-quinoline (12 grams, 82% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][NH:30][CH3:31]>O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:30]([CH3:31])[CH2:29][CH2:28][OH:27])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccccc4)ncnc23)CC1
Reactant: CNCCO
Solvent: C1COCCO1
Product: CN(CCO)c1nc(N2CCS(=O)CC2)c2ncnc(NCc3ccccc3)c2n1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylamino-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine (melting point: 232°-233° C.) and N-(2-hydroxy-ethyl)-methylamine in dioxane under reflux.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:20]=[CH:19][C:18]2OC3C(=CC=CC=3)NC=2C=1.[NH2:21][CH2:22]CC1CCCN1C.[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:20][CH2:19][CH2:18][N:21]1[CH3:22]
Reactant: CN1CCCC1CCN
Reactant: c1ccc(-c2ccc3c(c2)Nc2ccccc2O3)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCCC1c1ccccn1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
2-Pyridinyl phenoxazine (28 mg,), 2-(2-aminoethyl)-1-methylpyrrolidine (17 ul, 0.1173 mmol) and aluminum chloride (21 mg, 0.1575 mmol) were mixed in anhydrous dichloromethane (1 ml) and stirred for 1 h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3×10 ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 2-pyridinyl methylpyrrolidine (17.5 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][C:17]([OH:19])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:22]>>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C(CCC(=O)O)c1ccccc1-2
Reactant: O=S(Cl)Cl
Product: Cc1cccc2c1C(CCC(=O)Cl)c1ccccc1-2
Reaction time: 2 h

Procedure:
3-(1-Methylfluoren-9-yl)propionic acid (2.5 g, 9.9 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. Excess of thionyl chloride was removed under reduced pressure. The residual oil was used for the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](OC)=[O:19])=[CH:12][CH:11]=1>Cl>[CH2:1]([NH:8][C:18](=[O:19])[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: NCc1ccccc1
Agent: Cl
Product: O=C(CCc1ccc(O)cc1)NCc1ccccc1
Temperature: 150 °C
Yield: 98.1 %

Procedure:
Add benzylamine (32.0 mL, 293 mmol) to methyl 3-(4-hydroxyphenyl)propionate (7.01 g, 38.9 mmol) and heat to 150° C. for 18 h under nitrogen. Cool to room temperature and pour the reaction mixture into 5 N hydrochloric acid (200 mL) and extract with ethyl acetate (3× 150 mL). Wash the ethyl acetate extracts with 5 N hydrochloric acid (200 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 9.74 g (98%) of N-benzyl-3-(4-hydroxy-phenyl)-propionamide: mass spectrum (ion spray): m/z=256.2 (M+1); 1H NMR (DMSO-d6): 9.15 (s, 1H), 8.28 (t, 1H), 7.39-6.96 (m, 7H), 6.66-6.63 (m, 2H), 4.23 (d, 2H), 2.72 (t, 2H), 2.37 (t, 2H).
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([CH2:19][CH2:20][NH:21][C:10]([CH3:11])=[CH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: NCCN1CCOCC1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=CC(=O)c1ccccc1)NCCN1CCOCC1

Procedure:
A solution of 28.7 g. (0.177 mole) of benzoylacetone and 23.2 ml. (0.177 mole) of 2-(4-morpholinyl)ethylamine in 600 ml. of toluene was heated under reflux for ten and a half hours under a Dean-Stark trap and the solution then cooled and taken to dryness to give N-[2-(4-morpholinyl)ethyl]-N-(1-methyl-3-oxo-3-phenylpropenyl)amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[CH2:6]2
Reactant: O=Cc1ccncc1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2

Procedure:
Additionally, it is disclosed in Example 2, 4 and 6 of JP-A 8-225527 (1996) (EP-711,756-A1, U.S. Pat. No. 5,606,064) that reaction of 5,6-dimethoxy-1-indanone with pyridin-4-aldehyde afforded 5,6-dimethoxy-2-(pyridin-4-yl)methyleneindan-1-one (Example 2), followed by reaction with benzyl bromide afforded 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpiridinium bromide (Example 4), then reduction in the presence of platinum oxide afforded Donepezil (Example 6). According to this method, yield for Donepezil through Example 2, 4 and 6 was 58.5% (87%×83%×81%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:13](I)[CH3:14]>CN(C=O)C>[Cl:3][C:4]1[N:8]([CH2:13][CH3:14])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: CCI
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a cooled (0° C.) stirred suspension of NaH (60% dispersion in mineral oil; 7.08 g, 0.118 mol) in DMF (100 mL) was added 2-chlorobenzimidazole (15.00 g, 0.098 mol). The mixture was warmed to room temperature and stirred for 1 hour. Ethyl iodide (18.40 g, 0.118 mol) was added and stirring was continued for 3 hours. The mixture was poured onto the ice water and the resulting off-white solid was collected by filtration to give 10.0 g (61%) of product m.p. 48°-50° C.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][O:2]1.[BH4-].[Na+].O>C(O)C>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][O:2]1
Reactant: O=C1CCC2(CCOC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCC2(CCOC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-oxaspiro[4.5]decan-8-one (46.4 g., 0.3 mole) from Part C above in 1.5 liters of absolute ethanol was stirred under N2 atmosphere while sodium borohydride was added in 1-1.5-g. portions. When the addition was completed the mixture was stirred at room temperature for 4 hours. Then 1445 ml. of water was added and stirring was continued for 30 minutes. Ethanol was removed in vacuo and the aqueous layer was extracted with chloroform to give 43 g. (91%) of a mixture of two isomers by TLC analysis and NMR spectral analysis. H-NMR δ (ppm) 1.02-1.79 (10H, multiplet); 3.24-3.95 (5H, multiplet); mass spectrum m/e 156 (M+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) in 1,4-dioxane (3 ml) were sequentially added N,N-diisopropylethylamine (0.34 ml) and benzoyl chloride (0.05 ml), and the solution was stirred for 1 hour at 100° C. The solution was let to cool down, then a saturated aqueous solution of sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with an aqueous solution of 10% citric acid and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate-tetrahydrofuran system) to provide the title compound (133 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[O:31]1[C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:36]([C:35]5[O:31][N:32]=[CH:33][CH:34]=5)=[O:37])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: O=C(O)c1ccno1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)c3ccno3)CC2)n1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 55) was coupled with isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 523.1 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]([C:21]2[C:29]3[CH:28]=[C:27]([C:30]4[C:35](C)=[CH:34][N:33]=[C:32]([Cl:37])[N:31]=4)[S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:38]C1C(C2SC3C=CC=C(C(O)=O)C=3C=2)=NC(Cl)=NC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]([C:21]2[C:29]3[CH:28]=[C:27]([C:30]4[C:35]([Br:38])=[CH:34][N:33]=[C:32]([Cl:37])[N:31]=4)[S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4C)cc23)c2ccc(OC)cc2)cc1
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Product: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4Br)cc23)c2ccc(OC)cc2)cc1

Procedure:
Using the method of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid [bis-(4-methoxyphenyl)-methyl]-amide, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid as a tan solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[BH4-].[Na+]>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10]
Reactant: O=C1Cc2ccccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1Cc2ccccc2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A 60 g sample of 2-indanone (0.45 moles) in 1.5 liters of 40% aqueous methanol was treated with 18 g (0.46 moles) of sodium borohydride in portions with cooling to maintain T≤ 40°C. After the addition was complete (15 min), the mixture was stirred for 2 hrs then allowed to stand overnight at room temp. Ether extraction, drying over potassium carbonate and evaporation gave 58.3 g crystalline 2-indanol (96%).