Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:16])=[NH:15])=[N:6]1.[C:21](/[C:23](/[N:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[CH:24]\[O-])#[N:22].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:22][C:21]1[C:23]([N:26]([CH3:27])[C:28](=[O:29])[O:30][CH3:31])=[CH:24][N:16]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: COC(=O)N(C)/C(C#N)=C/[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)N(C)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C

Procedure:
Under argon, 0.80 g (2.61 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine from Example 6A, 0.51 g (2.86 mmol) of sodium (E)-2-cyano-2-[(methoxycarbonyl)(methyl)amino]ethenolate from Example 10A and 0.53 g (0.73 ml, 5.23 mmol) of triethylamine are added to 50 ml of toluene. The mixture is heated under reflux for 9 hours. It is then cooled to RT again and is mixed and extracted with dichloromethane and water. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo in a rotary evaporator. The residue is mixed with 5 ml of diethyl ether and crystallizes therewith. The crystals are filtered off with suction, dried and purified by preparative RP-HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-])=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-n2cnc3c[n+]([O-])ccc32)cc1
Product: O=[N+]([O-])c1ccc(-n2cnc3c(Cl)nccc32)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
In 5 mL of phosphorus oxychloride, 42 mg (0.164 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine 5-oxide was dissolved and the solution was stirred at 80° C. for 14 hours. Excess reagent was distilled under reduced pressure, and the residue was partitioned between ethyl acetate (10 mL×2) and a sodium hydrogencarbonate aqueous solution (10 mL). The combined organic layers were washed with a saturated sodium chloride solution, dried on anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was separated by a silica gel column (Si-10, a product of Kusano Co., Ltd., column 30 cm, dichloromethane:methanol=19:1) to obtain 45 mg (quantitative) of 4-chloro-1-(4-nitrophenyl)-1H-imidazo-[4,5-c]pyridine as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([NH2:17])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:8]=1.C1C(=O)N([I:27])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[C:4]([NH2:17])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16]([I:27])[N:11]3[N:10]=2)[CH:8]=1
Reactant: Nc1ncc(-c2nn3ccnc3s2)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2nn3c(I)cnc3s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
3-(trifluoromethyl)-5-(imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-2-amine (0.244 g, 0.855 mmol, 1 eq) was dissolved in DMF (5 mL), and NIS (0.212 g, 0.941 mmol, 1.1 eq) was added. The reaction mixture was stirred at RT under N2 for 18 h and then poured into an aqueous solution of sodium thiosulfate (10%) and extracted with AcOEt. The organic phase was separated, washed with ice-water and ammonium chloride, dried (Na2SO4), filtered and evaporated to dryness. The residue was treated with Et2O, filtered off and dried affording the desired product (0.240 g, 68%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.27 min, [M+H]+ m/z 411.9.
Reaction SMILES: I[CH3:2].[CH2:3]([N:10]1[CH:16]2[CH2:17][CH2:18][CH:11]1[CH2:12][NH:13][CH2:14][CH2:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CCOCC>[CH2:3]([N:10]1[CH:16]2[CH2:17][CH2:18][CH:11]1[CH2:12][N:13]([CH3:2])[CH2:14][CH2:15]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2C3CCNCC2CC3)cc1
Reactant: CI
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCC2CCC(C1)N2Cc1ccccc1

Procedure:
Neat Iodomethane (0.173 ml, 2.77 mmol) was added dropwise to a stirred solution of 9-benzyl-3,9-diazabicyclo[4.2.1]nonane (0.4 g, 1.849 mmol) and TEA (2.58 ml, 18.49 mmol) in THF (5 ml). The resultant suspension was stirred at rt for 3 hrs and diluted with ether and then filtered. The filtrate was evaporated to dryness to afford 9-benzyl-3-methyl-3,9-diazabicyclo[4.2.1]nonane as a light yellow oil. LC/MS: m/e 231 (MH+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1)[CH3:14].CI>O1CCCC1>[CH2:13]([O:15][C:16](=[O:23])[CH:17]([CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1)[CH3:1])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CC1CCOC1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1CCOC1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A stirred solution of N,N-diisopropylamine (2.38 mL, 17.0 mmol) in anhydrous tetrahydrofuran (40 mL) was cooled to −20° C. before adding n-butyllithium (6.3 mL, 15.8 mmol, 2.5 M in hexanes). The reaction was allowed to warm to −10° C. for 10 minutes then cooled to −78° C. A solution of (tetrahydro-furan-3-yl)-acetic acid ethyl ester (1.23 g, 7.77 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred for 2.5 h at −78° C. and then methyl iodide (3.92 mL, 63.2 mmol) was added. The reaction was stirred for 15 h gradually warming to room temperature. The reaction was quenched with a saturated aqueous ammonium chloride solution (60 mL) and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title product (0.87 g, 65%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.13-1.30 (m, 6H), 1.51-1.69 (m, 1H), 1.96-2.11 (m, 1H), 2.29-2.51 (m, 2H), 3.39-3.48 (m, 1H), 3.67-3.80 (m, 1H), 3.81-3.95 (m, 2H), 4.08-4.20 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:55])([F:54])[F:56])[CH2:52][N:44]2[C:43]1=[O:57])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CC[C@H](C(F)(F)F)CN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((4S,8S,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 60 (6.3 mg, 0.023 mmol) to give a white solid (10 mg, 65% yield). Anal. Calcd. for C41H51F3N4O6S2 m/z 816.4. found: 817.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.05 (m, 10H), 6.87 (d, J=6.3 Hz, 2H), 5.33 (t, J=4.6 Hz, 1H), 5.22-5.07 (m, 2H), 5.05-4.93 (m, 1H), 4.84-4.71 (m, 1H), 4.37 (d, J=14.8 Hz, 1H), 3.69 (s, 3H), 3.33-3.10 (m, 3H), 2.92-2.51 (m, 7H), 2.48-2.20 (m, 4H), 2.12-1.92 (m, 3H), 1.93-1.76 (m, 2H), 1.77-1.19 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-])=O)=[N:9][CH:10]=1>C(O)C.ClCCl.[Pd]>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(C(F)(F)F)ccc2Cl)cn1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(Oc2cc(C(F)(F)F)ccc2Cl)cn1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
10% Pd/C (38 mg, 35 μmol, 10 mol % Pd) was added to chloride 3 (113 mg, 353 μmol) in ethanol:dichloromethane (3:1, 4.0 mL). The mixture was degassed and placed under H2 (1 atm) and stirred for 1 h. The mixture, filtered through a 0.45 μm syringe filter and concentrated under reduced pressure provided 4 (98.1 mg, 96%) as a solid: LRESIMS m/z 289.4 [M+H]+, calcd. for C12H9Cl1F3N2O1 289.0.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH3:12])=[C:6]([N:26]2[CH:30]=[CH:29][CH:28]=[CH:27]2)[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH3:12])=[C:6]([N:26]2[CH:30]=[CH:29][CH:28]=[CH:27]2)[CH:5]=1
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1-n1cccc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(N)cc1-n1cccc1)CCc1ccc(N)cc1
Yield: 99 %

Procedure:
1-[4-Nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-nitrophenethyl)-N-methylamino]ethane (0.71 g, 1.73 mmol) was dissolved in 80 ml of a 1:1 solvent system of ethyl acetate and methanol and, after slowly adding 10% Pd/C (0.2 g), the solution was stirred at an ordinary temperature for 3 h as hydrogen gas was injected. Thereafter, the reaction mixture was filtered through Celite and the filtrate was evaporated to yield the compound 1-[4-amino-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-aminophenethyl)-N-methylamino]ethane (0.6 g) as a dark brown oil. The compound was dissolved in pyridine (30 ml) and, thereafter, the solution was cooled at 0° C. and methanesulfonyl chloride (0.344 ml, 4.45 mmol) was slowly added. Thereafter, the mixture was stirred at an ordinary temperature for 20 h and ethanol was added; the solvent pyridine was evaporated under vacuum and the resulting residue was added to an aqueous solution of 10% sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed with water twice, dried with magnesium sulfate, and the solvent was evaporated. The residue was purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing 5% methanol. The fractions containing the product were collected and the solvent was evaporated to yield the titled compound 1-[4-methanesulfonamido-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane (0.43 g) as a pale yellow substance.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[N:8][C:7]([OH:10])=[N:6]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:18]Cl>C(O)C>[CH2:1]([N:5]1[C:9]([Cl:18])=[N:8][C:7]([OH:10])=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cnc(O)n1
Reactant: ClCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)Cn1nc(O)nc1Cl
Temperature: 25 °C

Procedure:
241 g of 1-isobutyl-3-hydroxy-1,2,4-triazole and 475 ml of triethylamine are dissolved in 2100 ml of absolute ethanol, and 182 g of chlorine are passed in while cooling at 20°-30°C. The solution is stirred for 1 1/4 hours at room temperature, after which the triethylamine hydrochloride is filtered off. The filtrate is concentrated in a rotary evaporator, the residue dissolved in 1000 ml of ether and 1000 ml of water are added. The phases are separated and the aqueous phase is extracted 3 times with 300 ml of ether each time. The ether phase is dried and concentrated. The residue is recrystallised from ligroin/xylene. Yield: 104.7 g (34 % of theory); m.p. 84°-86°C.
Reaction SMILES: O=C1C2C(=CC=CC=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH:21]=2)[NH:16][CH:15]=1.[OH2:27].NN>C(O)C>[C:20]1([CH2:23][O:27][C:4]([NH:3][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH:21]=3)[NH:16][CH:15]=2)=[O:11])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O
Agent: NN
Solvent: CCO
Product: NC(=O)Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetamide (17.55 g) and hydrazine hydrate (12 ml) in ethanol (700 ml) was heated at reflux for 2 h. The resulting suspension was cooled to ambient temperature and all the solvent was evaporated in vacuo. The resulting yellow solid was dissolved in dilute sodium hydroxide (250 ml) and tetrahydrofuran (100 ml) and treated with benzylchloroformate (21 ml) at 5°. Stirring was continued for 1 h at ambient temperature, reaction mixture extracted with ethylacetate (4×200 ml), dried (MgSO4) and solvent removed to give crude product as an oil which on trituration with ethylacetate gave the title compound as a white solid (6.4 g) m.p. 124°-5°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[O:14][C:13](=O)[CH:12]=1.[Cl-].[Li+].CO>ClCCl>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]2[C:15]([CH3:17])=[CH:16][C:11]([OH:10])=[CH:12][C:13]2=[O:14])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1cnc(Cl)cc1N
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Temperature: 160 °C
Yield: 6 %

Procedure:
A well-powdered mixture of 4-amino-5-methyl-2-chloropyridine (0.5 g, 3.5 mmol), 4-hydroxy-6-methyl-pyrone (0.665 g, 5.3 mmol), and lithium chloride (0.025 g, 0.6 mmol) was heated at 160° C. for 20 min in a sealed tube. The resulting melt was cooled and the product was isolated by silica gel flash chromatography using 3% methanol in dichloromethane. Appropriate fractions were combined, concentrated under reduced pressure and the resulting solid was triturated with ethyl acetate, cooled and filtered. The solid was washed with ethyl acetate and dried to give 0.053 g of the title compound as a yellow powder. ES-MS: m/z=251 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution resulting from 206 mg. (1 m mole) of 3-hydroxy-5-trifluoromethylbenzoic acid* and 85 mg. (2 m moles) of a 56.6% oil suspension of sodium hydride in 2 ml. of dimethylsulfoxide is added 127 mg. (1 m mole) of benzyl chloride and the reaction mixture heated to 90° C. for 1-2 hours. The mixture is cooled to room temperature, diluted with 10 ml. of water and extracted with ether. The aqueous phase is separated and acidified with 6N hydrochloric acid. The precipitated produce is filtered, dried and sublimed at 125° C. and .05 mm pressure, m.p. 143°-145° C.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC)(OC)OC.[CH3:21][C:22]([CH3:27])([CH2:25]O)[CH2:23][OH:24]>>[CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]32[O:24][CH2:23][C:22]([CH3:27])([CH3:25])[CH2:21][O:13]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(CO)CO
Reactant: O=C1CCCCC1C1CCCCC1
Solvent: COC(OC)OC
Product: CC1(C)COC2(CCCCC2C2CCCCC2)OC1

Procedure:
1.170 g (6.5 mols) of 2-cyclohexyl-cyclohexanone are reacted with 757.9 g (7.15 mols) of trimethyl orthoformate and 743.6 g (7.15 mols) of anhydrous 2,2-dimethyl-1,3-propanediol in a manner analogous to that in Example 1:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:31])C(=O)C1>C(#N)C>[C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][C:12]([Br:31])=[C:11]([CH3:15])[N:10]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Solvent: CC#N
Product: Cc1nc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1Br
Temperature: 40 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl[tert-butoxycarbonyl(6-methylpyridin-2-yl)amino]-acetate (477 mg, 1.48 mmol) obtained in Reference Example 1-(a) in acetonitrile (3 ml) was added NBS (398 mg, 2.24 mmol), followed by stirring at 40° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=20:1→5:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (565 mg) as a white solid. (Yield: 95%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:21])([CH3:20])[N:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]O)[CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:18][C:16]1[CH:17]=[C:12]([N:7]2[C:6]([CH3:21])([CH3:20])[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH:13]=[N:14][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)c2ccc(F)cc2C(=O)N1c1cncc(CO)c1
Solvent: ClCCl
Product: CC1(C)c2ccc(F)cc2C(=O)N1c1cncc(CCl)c1
Temperature: 3.5 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
To a solution of 6-fluoro-2-(5-hyroxymethyl-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (52 mg) in DCM (10 mL) was added thionyl chloride (0.14 mL, 1.9 mmol) slowly at 0° C. After the addition, the reaction mixture was stirred at 2-5° C. for 0.5 hour before it was poured into satd. aq. NaHCO3 solution (10 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (58 mg 100%) as light yellowish solid. MS: 322.1 (M+H+).
Reaction SMILES: [CH:1]([C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:5])([CH3:3])[CH3:2].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:7]1[N:8]=[C:9]([NH:11][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:24])[S:10][C:6]=1[C:4](=[O:5])[CH:1]([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)C(=O)c1sc(N)nc1-c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
Compound 392 (100 mg, 0.424 mmol) was dissolved in DMF (5 mL), and isonicotinic acid (205 mg, 1.68 mmol), EDC hydrochloride (324 mg, 1.69 mmol) and 1-hydroxybenzotriazole monohydrate (259 mg, 1.69 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 393 (103 mg, 71%) as a pale green solid.
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]([O:19]C)=[O:18])=[CH:9]1.Cl>CO.O>[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]([OH:19])=[O:18])=[CH:9]1
Reactant: COC(=O)c1cn(-c2nccs2)c2ncccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(-c2nccs2)c2ncccc12
Temperature: 100 °C

Procedure:
Potassium hydroxide (38.5 mg, 0.687 mmol) was added to a solution of methyl 1-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (35.6 mg, 0.137 mmol) in MeOH (343 μl) and water (343 μl) at RT. The mixture was heated at 100° C. for 2 h. After cooling to RT, the mixture was acidified with 2 N HCl and then concentrated under reduced pressure. The crude mixture was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.CN(C)P(N(C)C)(N(C)C)=O.C(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([Cl:23])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: Cc1ncsc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ncsc1C(=O)Cl
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 7.2 g (0.05 mole) of 4-methylthiazole-5-carboxylic acid were suspended in 100 ml of toluene, followed by the addition of 0.02 g of hexamethylphosphoramide Under heating and reflux, phosgene was blown at a rate of 1.2 l/hr for 2.5 hours (0.13 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 8.0 g of 4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 99.2% an d99.0%, respectively. NMR (δCDCl 3/TMS, ppm): 2.88(3H,s).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[BH4-:8].[Na+:9]>>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][BH3-:8])=[O:4].[Na+:9]
Reactant: O=C(O)C(F)(F)F
Reactant: [BH4-]
Agent: [Na+]
Product: [BH3-]OC(=O)C(F)(F)F

Procedure:
Sodium trifluoroacetoxyborohydride was prepared in situ from trifluroacetic acid and sodium borohydride, which means the operation was carried out in a single pot.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: COc1ccccc1CCN
Reactant: CC(=O)OC(C)=O
Product: COc1ccccc1CCNC(C)=O

Procedure:
In close analogy to the procedure described above, 2-(2-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.