Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCOCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCCOCCCC=O
Temperature: -45 °C
Yield: 77.4 %

Procedure:
A solution of oxalyl chloride (42 mL) in dry methylene dichloride (750 mL) was cooled under a nitrogen atmosphere to −75° C. Dimethylsulfoxide (72 mL) was added dropwise with stirring, followed after 10 minutes by a solution of 4-(n-heptyloxy)butan-1-ol (75.2 g from below) in methylene dichloride (75 mL). The mixture was stirred and allowed to warm to −45° C., then was again cooled to −75° C. and treated dropwise with triethylamine (292 mL). After the addition was complete, the cooling bath was removed and the mixture was allowed to slowly warm to room temperature and stir one hour. Ice was added, and the product was partitioned between water and methylene dichloride. The solvent was removed with a rotary evaporator, and the residue was dissolved in petroleum ether (500 mL) and the solution was rinsed in water, cold aqueous hydrochloric acid, water, and saturated aqueous sodium bicarbonate. After drying over magnesium sulfate, the solvent was stripped in vacuo, and the residue was distilled to give 57.6 g (77%) of 4-(n-heptyloxy)butanal, b.p. 60° C., 0.26 Torr.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([C@@:30]1([CH3:56])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N+:32]2[C@@H:50]([CH:53]3[CH2:55][CH2:54]3)[CH2:51][O:52][C:31]1=2)[CH:28]=[CH2:29]>O1CCCC1.O>[CH2:27]([C@@:30]1([CH3:56])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N:32]([C@@H:50]([CH:53]2[CH2:55][CH2:54]2)[CH2:51][S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:31]1=[O:52])[CH:28]=[CH2:29]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Reactant: CC(C)(C)S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSC(C)(C)C)C2CC2)C1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-2-propanethiol (0.195 mL, 1.796 mmol, dried over activated 4 Å molecular sieves) was added to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 1.8 mL, 1.8 mmol) in anhydrous tetrahydrofuran (4 mL) at room temperature. The reaction mixture was heated at 60° C. After 15 minutes at 60° C., (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-α]pyridin-4-ium 4-methylbenzenesulfonate (1.00 g, 1.632 mmol, Example 1, Step F) was added as a solid. The reaction mixture was heated at 60° C. for 12 hours and then cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate thrice and the organics were pooled, washed with brine, dried over sodium sulfate, decanted and concentrated under a vacuum to provide a brown oil. Purification by flash chromatography (80 g SiO2 column, gradient elution of 10 to 60% ethyl acetate in hexanes provided the desired product as a colorless syrup.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([O:4][C@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:25])[C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CO)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a stirred suspension of (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (6.35 g, 18.8 mmol) and potassium carbonate (5.2 g, 38 mmol) in dimethylformamide (55 ml) was added methyl iodide (4.0 g, 28.2 mmol). After stirring overnight at room temperature, the mixture was poured into ice cold water (250 ml) and stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (5×25 ml), and dried under vacuum to provide (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3,7-dimethylxanthine (6.3 g, 95% yield) as a white solid.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[C:7]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.O.CO>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:7]2[C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[C:5]([OH:25])=[O:4])=[O:24])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(NC(=O)c2ccc(F)cc2)c1C
Temperature: 50 °C
Yield: 101.4 %

Procedure:
LiOH (1M, 4 mL) was added to a solution of 2-(4-fluoro-benzoylamino)-4-methoxy-3-methyl-benzoic acid methyl ester (90) (870 mg, 2.7 mmol), in tetrahydrofuran (15 ml), water (7.5 ml) and methanol (7.5 ml). The mixture was heated to 50° C. for 4 h. Water (30 ml) was then added and the volume reduced to half. Acidification with acetic acid followed by filtration gave pure title compound (830 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH3:19])[C:6]([CH:8]=[CH:9][C:10](O)=[O:11])=O.C(=O)([O-])[O-].[K+].[K+].Cl.O.[NH2:28][NH2:29]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH:8]=[CH:9][C:10](=[O:11])[NH:28][N:29]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH3:19]
Reactant: NN
Reactant: CCCOc1ccc(C(=O)C=CC(=O)O)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.6 g of 3-(3-methoxy-4-n-propoxybenzoyl)acrylic acid and 6.1 g of potassium carbonate are dissolved in 100 ml of methanol and the solution is stirred overnight at room temperature. It is acidified with 7.4 ml of concentrated hydrochloric acid, 2.2 g of 100% pure hydrazine hydrate are added to the mixture and the mixture is boiled under reflux for 3 hours. It is then acidified to pH 1 with 1 ml of hydrochloric acid and 75 ml of methanol are distilled off in the course of 2 hours. The mixture is allowed to cool and the crystal mass is filtered off with suction, suspended several times in 50 ml of water each time, filtered off with suction and, finally, dried in vacuo. 6.6 g (63.7% of theory) of the title compound of m.p. 169°-171° are obtained. After recrystallization from ethanol/ethyl acetate, the m.p. rises to 172°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:14]([C:3]1[CH:4]=[CH:5][C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])=[CH:7][C:2]=1[NH:1][C:24](=[O:26])[CH3:25])(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(S(F)(F)(F)(F)F)cc1N
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(S(F)(F)(F)(F)F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[2-Amino-4-(pentafluorosulfanyl)phenyl]ethanone (150 mg, example 19d) was dissolved in methylene chloride (5 ml). After adding triethylamine (95 μl) and acetyl chloride (51 μl), the mixture was stirred at RT for 4 h. Then methylene chloride, water and saturated sodium hydrogencarbonate solution were added. The organic phase was removed, washed three times with water, dried over magnesium sulfate, filtered and concentrated. 165 mg of the desired product were obtained.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([F:50])=[CH:29][C:30]([Cl:49])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[Cl:49][C:30]1[C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:46][CH2:47]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:48][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5]3)[CH:7]=2)=[C:28]([F:50])[CH:29]=1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c(Cl)cc3F)c2)CC1
Yield: 71.8 %

Procedure:
Using 3-(1-cyanocyclopropyl)benzoic acid (100 mg, 0.50 mmol), oxalyl chloride (55 μL, 0.62 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (160 mg, 73%) was obtained as a white powder.
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[C:7](=[O:15])[N:6]([CH3:16])[CH:5]=1.[CH3:17][S:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:15])[N:6]([CH3:16])[CH:5]=[C:4]2[C:26]1[CH:27]=[C:22]([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])[CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cn1cc(Br)c2cc(F)ccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)c2cc(F)ccc2c1=O
Yield: 50 %

Procedure:
For about 3 min N2 was bubbled through a mixture of 4-bromo-6-fluoro-2-methylisoquinolin-1-one (41 mg, 0.16 mmol), (3-methanesulfonamidophenyl)boronic acid (38 mg, 0.18 mmol), aqueous 1 M K3PO4 (0.3 mL) and Pd(dppf)Cl2 (12 mg, 0.016 mmol) in dioxane (1.2 mL) which was then microwaved for 1 h at 120° C. Work up was similar to that described for Example 18, step 3. Purification using silica gel chromatography, eluting with 40-80% EA in hexane over 5 min and continuing 80% isocratic EA gave the title compound (28 mg, 0.08 mmol) as a cream solid in a combined yield of 38% over steps 1-3. 1H NMR (400 MHz, DMSO-d6) δ 3.06 (s, 3H), 3.56 (s, 3H), 7.15-7.22 (m, 2H), 7.25-7.31 (m, 2H), 7.41 (td, J=8.65, 2.65 Hz, 1H), 7.45-7.52 (m, 1H), 7.61 (s, 1H), 8.40 (dd, J=9.09, 6.06 Hz, 1H), 9.88 (s, 1H). LCMS (M+H)+ 347.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[N:11]=1>C(#N)C>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5](=[S:6])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][C:5](=[S:6])[NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])[N:11]=1
Reactant: Nc1cccc(CO)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: FC(F)(F)CNC(=S)Nc1cccc(COC(=S)NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 19.7 %

Procedure:
2,2,2-Trifluoroethylisothiocyanate (2.82 g.) was added to a solution of 2-amino-6-hydroxymethylpyridine (2.1 g.) in acetonitrile (20 ml.) and the solution kept at room temperature for 18 hours and then evaporated to dryness. The residue was partitioned between ethyl acetate and water and the ethyl acetate phase separated, dried and evaporated to dryness. The residue was recrystallised from ethanol to give 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-[N-(2,2,2-trifluoroethyl)-thiocarbamoyloxymethyl]pyridine (0.8 g.), m.p. 173°-175°.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16]>>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: ClCCCCBr
Reactant: Oc1nc2ccccc2s1
Product: ClCCCCOc1nc2ccccc2s1

Procedure:
2-hydroxybenzothiazole (0.2 g, 1.32 mmol) and 1-bromo-4-chlorobutane (0.227 g, 1.32 mmol) were reacted in the same manner as in Example 1 to afford the compound K24 (0.302 g, 94%).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:43])([F:42])[CH2:25][O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52]>>[Cl:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[CH2:45][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][CH2:25][C:24]([F:42])([F:23])[F:43])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]3)[C:30]2=[N:35]1
Reactant: Clc1ccccc1CBr
Reactant: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3[nH]nnc23)C1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3nn(Cc4ccccc4Cl)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)-1-[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 429.4 (MH+).
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=O)=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[OH:51][C@H:48]1[CH2:49][CH2:50][N:46]([C:19]([C:16]2[N:8]3[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)[C:7]3=[N:18][CH:17]=2)=[O:21])[CH2:47]1
Reactant: O=C(O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(1,3-Oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (1.77 g) was dissolved in DMF (22 mL), and HATU (2.72 g), (S)-pyrrolidin-3-ol (529 μL) and triethylamine (1.08 mL) were added thereto. The reaction mixture was stirred at room temperature for 1 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a solid (1.38 g). The solid (100 mg) was recrystallized from ethyl acetate/hexane to give the title compound (89 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][OH:23])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>CO.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][O:23][CH2:26][CH2:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
A mixture of (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methanol (50 mg, 0.161 mmol), tert-butyl acrylate (0.059 mL, 0.403 mmol), and Triton B (40% in MeOH) (7 μL, 0.016 mmol) in toluene (1 mL) was stirred at rt for 5 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-30% EtOAc:hexanes) to afford the title compound (61 mg, 85% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.28 (dd, J=9.1, 6.7 Hz, 1H), 7.19-7.13 (m, 2H), 7.12-7.07 (m, 1H), 7.01 (ddd, J=4.4, 3.3, 1.8 Hz, 2H), 6.86 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 3.92 (s, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.17 (s, 2H), 2.48 (t, J=6.3 Hz, 2H), 2.10-1.95 (m, 4H), 1.86-1.73 (m, 2H), 1.70-1.58 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN[C@@H]3CCN(Cc4ccccc4)C3)cc2)nc1
Yield: 30.9 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), (3R)-1-benzylpyrrolidin-3-yl amine (0.22 mL, 1.27 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.154 g (31%) of the title compound as a white foam (chromatography solvent:ethyl acetate→4:1 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C24H27N4O2 403.2134, found 403.2131; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H), 7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3 Hz), 3.79 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J=12.7 Hz), 3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t 2H, J=6.8 Hz), 2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:49])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=S)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.9 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.052 mmol) and Lawesson's Reagent (40 mg, 0.09 mmol) in THF (1 mL) was stirred at room temperature for 3 h, then purified by flash column to give the title compound as white solid (7 mg).
Reaction SMILES: [CH2:1]([C@H:8]([NH:48]C(=O)OC(C)(C)C)[CH2:9][C@H:10]([OH:47])[C@@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:48][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C@H:10]([OH:47])[C@@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccc(-c4ccccn4)cc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccc(-c4ccccn4)cc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 132A (0.017 g, 0.023 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at 25° C. for 1 hour, and concentrated. The residue was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the product, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:17])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[CH2:10]1.ClC1C=C(C=CC=1)C(O)=[O:23]>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:17])[CH2:13][CH2:12][N+:11]([O-:23])([CH2:14][CH2:15][CH3:16])[CH2:10]1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCCN1CCC(O)(c2cccc(F)c2F)C1
Solvent: ClCCl
Product: CCC[N+]1([O-])CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 68: (−)-3-(2,3-difluorophenyl)-1-propylpyrrolidin-3-ol (1.3 g, 5.4 mmol), dichloromethane (60 ml), m-chlorobenzoic acid (2.7 g, 16.2 mmol). Yield: 1.15 g. 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.06 (t, J=7.41 Hz, 3H) 1.96-2.16 (m, 2H) 2.69-2.83 (m, 1H) 2.84-3.00 (m, 1H) 3.35 (dt, J=10.92, 5.46 Hz, 2H) 3.50 (br. s., 2H) 3.67 (d, J=9.75 Hz, 1H) 3.77 (d, J=10.92 Hz, 1H) 3.89-3.99 (m, 1H) 7.18 (d, J=1.56 Hz, 1H) 7.13-7.20 (m, 1H) 7.62 (td, J=6.63, 5.46 Hz, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>C(O)(=O)C>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:10][CH:11]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]2[N:4]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: Cc1nc2nccc(-c3cccnc3)n2n1
Yield: 40.3 %

Procedure:
A reaction mixture of 0.98 g of 3-amino-5-methyl-1,2,4-triazole and 1.76 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one in 25 ml of glacial acetic acid was refluxed for six hours. The procedure was continued as for Example 1 to give 0.85 g of the product of the Example as colorless crystals, mp 244°-245° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=2)[CH:19]=[O:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:22][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:18]([CH:19]=[O:20])[CH:21]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(N2CCN(Cc3ccccc3)CC2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C=O
Yield: 70 %

Procedure:
0.5 g of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde are dissolved in 5 ml of NMP at 20° C. under nitrogen with stirring, and 0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate are added. The mixture is stirred at 110° for 4 hours and cooled to 15°. 30 ml of water and 30 ml of ethyl acetate are added to the mixture, the phases are separated, and the aqueous phase is extracted with 30 ml of ethyl acetate. Combined organic phases are washed with 2×30 ml of water and freed from solvent under reduced pressure. The yellow oil which remains (0.7 g) is chromatographed on 10 g of silica gel (MTB ether/heptane 5:1) and gives 0.45 g of product (70%; yellowish oil), MS 382 (M+), 296, 263, 199, 149, 119, 91 (100%).