Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:23]([Br:24])=[CH:22][C:5]2[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl>[Br:24][C:23]1[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N)c(Br)cc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 6-amino-5-bromo-2-(2,4-difluorophenyl)benzofuran-3-carboxylate (310 mg, 0.78 mmol) and pyridine (185 mg, 2.35 mmol) in dichloromethane (10 mL) was added dropwise methanesulfonyl chloride (179 mg, 1.56 mmol) at 0° C., then the mixture was stirred at 25° C. overnight. 10% HCl (aq) was added, then the mixture was extracted with dichloromethane (30 mL*3), dried over Na2SO4, and concentrated to provide ethyl 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (350 mg, yield: 94%). 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.91 (s, 1H), 7.64˜7.90 (m, 1H), 7.06 (d, J=3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 6.88 (s, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.02 (s, 3H), 1.33 (t, J=7.6 Hz, 3H). MS (M+H)+: 474/476.
Reaction SMILES: CC1C(=O)NC(=O)N(C2OC(COC(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)C(O)C2)C=1.COP(Cl)[Cl:44].[N:46]1[C:51]([CH3:52])=[CH:50][C:49]([CH3:53])=[CH:48][C:47]=1[CH3:54].N1C=NN=N1>O1CCCC1>[ClH:44].[N:46]1[C:51]([CH3:52])=[CH:50][C:49]([CH3:53])=[CH:48][C:47]=1[CH3:54]
Reactant: COP(Cl)Cl
Agent: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: Cl
Reaction time: 0.25 h

Procedure:
5'-O-Dimethoxytritylthymidine (1.6 g, 2.9 mmol) in anhydrous tetrahydrofuran (5 ml) was added dropwise to a well stirred solution at -78° of CH3OPCl2 (0.33 ml, 2.5 mmol) and collidine (1.86 ml, 14.1 mmol) in anhydrous tetrahydrofuran (5 ml). A white precipitate formed during the addition. The mixture was stirred for 15 min at -78° and then filtered through a sintered glass funnel to remove collidine hydrochloride. The collidine hydrochloride was washed with dry tetrahydrofuran (1 ml). The filtrate was then diluted with dry toluene and concentrated to a gum. After dry argon had been bled into the apparatus, a solution (6 ml) containing toluene:tetrahydrofuran (2:1) was added and the gum was allowed to dissolve completely in this solution. Solvent was removed by concentration in vacuo. This reconcentration using a solution of toluene and tetrahydrofuran was repeated three times. After the final concentration, the gum was dissolved in dry tetrahydrofuran (3 ml), cooled to -78° and a solution of tetrazole (0.18 g, 2.6 mmol) in dry tetrahydrofuran (3 ml) was added dropwise. A white precipitate of collidine hydrochloride formed during the addition. The mixture was stirred an additional 10 min at -78° and then transferred using positive argon pressure and a cannula to a centrifuge tube filled with argon. The supernatant recovered after centrifugation contained the tetrazolylphosphite product which can be used directly for synthesis of deoxyoligonucleotides. Alternatively, the tetrazolylphosphite can be stored as a precipitate and reconstituted as needed.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15]4[CH2:31][CH2:30][CH2:29][CH2:28][C:16]=4[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.C(O)C>CCOCC>[O:27]=[C:19]1[C:18]2[C:13](=[CH:14][C:15]3[CH2:31][CH2:30][CH2:29][CH2:28][C:16]=3[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)n2COCCOC)CCCC4)c1
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Yield: 48.3 %

Procedure:
Preparation of 1-(4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. HCl (4M in dioxane, 2.1 mL, 8.3 mmol) was added to a solution of 1-[3-(2-methoxy-ethoxymethyl)-4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.254 g, 0.596 mmol) and ethanol (2.0 mL). The reaction mixture was stirred at room temperature for 4 h, at which point ether (2 mL) was added and the precipitate was collected. The precipitate was triturated three times with ethanol, once with ethanol/THF (1:1), and once with DMSO. The filter cake was rinsed with ethanol and dried to yield the titled compound (89.4 mg, 44% yield). MS (ESI/Cl): mass calcd. for C18H18N4O3, 338.1; m/z found, 339.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.66 (s, 1H), 8.98 (s, 1H), 8.30 (s, 1H), 7.84 (s, 1H), 7.40 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.95-2.83 (m, 4H), 1.82-1.74 (m, 4H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=2[N:16]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][O:36][CH:37]1[CH2:40][NH:39][CH2:38]1>>[CH3:35][O:36][CH:37]1[CH2:40][N:39]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:11]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=3[N:16]=2)=[O:6])[CH2:38]1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(OC)C4)c3)nc12

Procedure:
From 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride. ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N:34]1([CH2:40][CH2:41][OH:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:37]4[CH2:38][CH2:39][N:34]([CH2:40][CH2:41][OH:42])[CH2:35][CH2:36]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: OCCN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-ethanol following General Procedure C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:15]=[CH:14][CH:13]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH:17]1([N:16]2[C:12]([NH:11][C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)c1ccccc1I
Reactant: Nc1ccnn1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Nc1ccnn1C1CCCC1
Temperature: 0 °C
Yield: 68.5 %

Procedure:
A mixture of 2-iodobenzoic acid (28 g, 0.113 mol), 5-amino-1-cyclopentylpyrazole (17 g, 0.113 mol), DMF (100 ml), potassium carbonate (16 g, 0.113 mol) and Cu(OAc) 2 (0.5 g) was refluxed overnight. The reaction mixture was poured into ice-water, and acidified with acetic acid to a pH of 5. The gum which formed was extracted with CH2Cl2 and the CH2Cl2 layer was washed with water, dried over MgSO4, and evaporated to afford 21 g of N-(1-cyclopentyl pyrazol-5-yl) anthranilic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=C[N:20](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[C:14]([C:11]1([CH3:17])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)(=[O:15])[NH2:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (2.85 g, 11.7 mmol) in DMF (57 mL) was added CDI (2.28 g, 14.1 mmol). The mixture was stirred at 60° C. for 30 minutes, then cooled to room temperature. Ammonium hydroxide (18.2 mL, 117 mmol) was added cautiously and stirring continued for 1 hour. The mixture was then evaporated to give a colourless oil. It was extracted with ethyl acetate and the organic layer washed with HCl (1 M), with water, sodium hydrogen carbonate solution, brine, dried over sodium sulfate, filtered and evaporated. The residue was taken up in toluene, then hexane was added and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered, washed with hexane and dried to give the title compound (2.55 g, 90%) as a white solid.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccncc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 46.7 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (230 mg, 0.78 mmol, 1.0 eq), L-isoleucine pyridin-4-ylmethylamide (266 mg, 1.5 mmol) and dichloromethane (2 mL), was treated with triethylamine (660 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (1.0 mL, 2.0 eq), to provide 180 mg (46%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] pyridin-4-ylmethylamide.
Reaction SMILES: [CH3:1][C:2]1([O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[C@H:5]1[O:6]CC1C=CC(Cl)=CC=1Cl)[O:3][CH3:4].Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1([O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[C@H:5]1[OH:6])[O:3][CH3:4]
Reactant: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Reaction time: 27 h

Procedure:
To a solution of the product of Step 1 (171.60 g, 0.2676 mol) in 1.8 L CH2Cl2 that was cooled to 0° C., was added dropwise a solution of stannous chloride (31.522 mL, 0.2676 mol) in 134 mL CH2Cl2 while stirring. After the solution was kept at 3° C. for 27 hours, another 5.031 ml of SnCl4 (0.04282 mol) was added and the solution was kept at 3° C. overnight. After 43 hours the reaction was quenched by carefully adding the solution to 1.9 L saturated NaHCO3 solution. Tin salts were removed via filtration through celite after which the organic phace was isolated, dried with MgSO4 and evaporated in vacuo. The yield of raw, dark yellow oil was 173.6 g, which contains 2,4-dibenzoyl chloride. The crude oil was used directly in the next step without further purification.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:40]#[N:41])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:42][O:43]C(=O)C)(=O)C.N.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Pd]>[NH2:41][CH2:40][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:42][OH:43])[O:7]2)=[C:19]([NH:23][CH2:24][CH:25]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Product: NCc1nc(NCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (700 mg, 1 mmol) (Preparation 64) in ethanol (20 ml) was saturated with ammonia gas. 10% Palladium on carbon (140 mg) was added and the reaction mixture stirred under an atmosphere of hydrogen gas (414 kPa, 60 psi) at room temperature for 16 hours. The Palladium on carbon was filtered off through Arbocel (Trade Mark) and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (50 ml) and sodium carbonate (60 mg, 0.57 mmol) was added. The reaction mixture was stirred for 1.5 hours and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:2 by volume). The solvent was removed under reduced pressure to give the title compound (275 mg) as a foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH3:15][NH2:16]>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:16][CH3:15])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-fluoro-3-nitrobenzoic acid methyl ester (507.3 mg, 2.55 mmol) in tetrahydrofuran (1 ml), methylamine (2.0 M tetrahydrofuran solution, 2.55 ml, 5.09 mmol) was added in an ice bath, and the mixture was stirred at room temperature overnight; The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (20 ml), and after washing in saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. It was then concentrated under reduced pressure, the obtained residue was dissolved in a methylamine-tetrahydrofuran solution (2.0 M, 3 ml), and upon sealing, the solution was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (30 ml), and the solution was washed with saturated aqueous sodium bicarbonate and brine and then dried over anhydrous magnesium sulfate. The dried product was concentrated under reduced pressure to obtain 4-methylamino-3-nitro-benzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[NH:25][NH2:26]>C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3](=[CH:12][NH:26][NH:25][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][C:19]=1[Cl:24])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=O)C(C#N)=CNNc1c(Cl)cc(Cl)cc1Cl

Procedure:
Four grams (18.9 mmol) of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is dissolved in hot ethanol/toluene. To this is added, portionwise, 4 g of 2,4,6-trichlorophenylhydrazine. The mixture is heated to reflux for three days. Cooling of the mixture and evaporation of the solvent gives the crude product, which is recrystallized from ethanol (3 X) to yield α-cyano-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide, m.p. =161° (dec.).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O-:5])=[O:4].[Na+].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>[Cl-].C[N+](C)(C)C.O>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:9][CH:11]1[O:13][CH2:12]1)=[O:4]
Reactant: ClCC1CO1
Reactant: CC(C)(O)C(=O)[O-]
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)C(=O)OCC1CO1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Into a 200 mL three-necked flask equipped with a stirrer and reflux tube was charged 37.83 g (0.3 mol) of sodium 2-hydroxyisobutyrate, 138.7 g (1.5 mol) of epichlorohydrin, 0.25 g of tetramethylammonium chloride and pure water at room temperature under normal pressure, and heated at temperatures from room temperature to an inner temperature of 120° C. over a period of 10 minutes, then, reacted while keeping this temperature for 1.5 hours, then, cooled to room temperature. To this was added water and allowed to stand for 1.5 hours, then, an organic solvent phase was removed. After epichlorohydrin was distilled off in a distillation apparatus equipped with a Vigreux distilling column, the obtained residual liquid was distilled under reduced pressure to obtain glycidyl 2-hydroxyisobutyrate. The charging molar ratio, reaction conditions and reaction yield, and the amount of by-products after distillation under reduced pressure are shown in Tables 1 and 2. The addition ratio of catalysts and water in the tables were calculated based on the total weight of a raw material compound of the formula (1), epichlorohydrin, catalyst and water.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:40]1[N:45]=[CH:44][C:43]([C:46]([NH:48][CH3:49])=[O:47])=[CH:42][CH:41]=1>CN(C)C=O>[CH3:49][NH:48][C:46](=[O:47])[C:43]1[CH:42]=[CH:41][C:40]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[N:45][CH:44]=1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47) in N,N-dimethylformamide (˜0.06 M) under a dry nitrogen atmosphere is placed in a microwave vial and stirred. Sodium hydride or a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.2 equivalents) is added to the reaction mixture and stirring is continued for 45 minutes. 6-Chloro-N-methyl-3-pyridinecarboxamide (CAS#54189-82-1, 1.2 equivalents) is added to the reaction mixture and stirring is continued for 2-3 hours at 100° C. under microwave irradiation with the cooling air remaining on for the duration of the heating cycle. The reaction mixture is cooled to ambient temperature, dried (MgSO4), and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel, eluting with 98:2 dichloromethane/2 M NH3 in methanol. Fractions containing product are combined and concentrated under reduced pressure to give (R)—N-methyl-6-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yloxy)nicotinamide.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH:5]=[CH2:6].[CH:8]([O:10][C:11](Cl)=[O:12])=[CH2:9]>>[CH:8]([O:10][C:11](=[O:12])[N:3]([O:2][CH3:1])[C:4](=[O:7])[CH:5]=[CH2:6])=[CH2:9]
Reactant: C=COC(=O)Cl
Reactant: C=CC(=O)NOC
Product: C=COC(=O)N(OC)C(=O)C=C

Procedure:
The synthesis was carried out analogously to synthesis example 8 using N-methoxy-acrylamide and chloroformic acid vinyl ester. Purification by column chromatography on silica gel (PE:EE=9:1) yielded 1.6 g (91% of th.) of the title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:21])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1ccccc1C(=O)Cl

Procedure:
First, octyloxybenzoic acid was heated in thionyl chloride under reflux until complete dissolution. Excess thionyl chloride was removed by vacuum distillation. Thus there was obtained octyloxybenzoic acid chloride.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]=2)[S:5][CH:6]=1.CC(C)([O-])C.[Na+].[CH2:41]([C@H:45]1[CH2:50][NH:49][CH2:48][CH2:47][N:46]1[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:42]([CH3:44])[CH3:43]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[CH2:41]([C@H:45]1[CH2:50][N:49]([C:2]2[N:3]=[C:4]([C:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[N:9]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:8]=3)[S:5][CH:6]=2)[CH2:48][CH2:47][N:46]1[C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH:42]([CH3:44])[CH3:43]
Reactant: Brc1csc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncccc23)n1
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H]1CN(c2csc(-c3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ncccc34)n2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 48.7 %

Procedure:
3-(4-bromothiazol-2-yl)-1-trityl-pyrazolo[5,4-b]pyridine (234 mg, 0.4470 mmol), sodium tert-butoxide (60.14 mg, 0.6258 mmol), tert-butyl (2S)-2-isobutylpiperazine-1-carboxylate (130.0 mg, 0.5364 mmol), Pd2 dba3 (4.093 mg, 0.004470 mmol) and RUPHOS (8.343 mg, 0.01788 mmol) in toluene (3 mL) were heated in microwave for 2 h at 100° C. Added more Pd2 dba3 (4.093 mg, 0.004470 mmol) and RUPHOS (8.343 mg, 0.01788 mmol) and heated at 100° C. for a further 1 h in microwave. Cooled to room temperature, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (12 g SiO2, 0 to 15% EtOAc/petrol) to leave product as a luminous green sticky oil (149 mg, 49%); 1H NMR DMSO-d6 δ 1.01 (dd, 6H), 1.53 (s, 9H), 1.69-1.57 (m, 2H), 1.81-1.76 (m, 1H), 2.80 (td, 1H), 2.94 (dd, 1H), 3.28 (t, 1H), 3.81 (d, 1H), 3.90 (d, 1H), 4.09 (br s, 1H), 4.37 (br s, 1H), 7.15 (dd, 1H), 7.28 (s, 16H), 8.29 (dd, 1H), 8.70 (dd, 1H); ES+ 685.47.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(C)=O.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc(F)c(F)c2)CC1
Yield: 48 %

Procedure:
A solution of 8-(3,4-difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (3 mmole) in acetone (100 ml) and concentrated HCl (1 ml) was reacted as described in example 25 to give the product (48%, mp: 84-85° C.). Calc'd for C12H12F2O2 : C, 63.72%; H, 5.35%. Found: C, 62.72%; H, 5.24%.