Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[P:2]([O-:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[CH2:10]=[O:11].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15](Cl)=[O:16]>C(OCC)C>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15]([O:11][CH2:10][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])=[O:16]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: C=O
Reactant: CCOP([O-])OCC
Agent: [Na]
Solvent: CCOCC
Product: CCOP(=O)(COC(=O)c1c(Cl)cccc1Cl)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a stirred solution of 5.8 grams (0.25 mole) of sodium metal in 150 ml of diethyl ether, under an argon atmosphere and at 15°-20°, was added dropwise 34.5 grams (0.25 mole) of diethyl phosphite. Complete addition required 60 minutes. Upon completion of the addition, the reaction mixture was kept at 15°-20° for 1 hour, then heated under reflux for 1 hour. The reaction mixture was cooled to 15° and 9.0 grams (0.30 mole) of paraformaldehyde was added in portions during a 10-15 minute period. Upon completion of the addition the reaction mixture was stirred at ambient temperature for 18 hours. After this period 52.4 grams (0.25 mole) of 2,6-dichlorobenzoyl chloride in 50 ml of diethyl ether was added dropwise during a 37-minute period. Upon completion of the addition the reaction mixture was stirred for 1.5 hours, then filtered. The filtrate was evaporated under reduced pressure to a residual oil. Impurities were removed from the residual oil by high vacuum distillation. The pot residue was subjected to column chromatography on 600 grams of silica gel using ethyl acetate as eluent. The appropriate fractions were combined and distilled under high vacuum to give 13.6 grams of diethyl (2,6-dichlorobenzoyloxy)methylphosphonate; bp 164°-167°/0.01 mm. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:10].[C:11]([S-:13])#[N:12].[K+].BrBr>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[CH:5][C:6]2[N:9]=[C:11]([NH2:12])[S:13][C:7]=2[CH:8]=1
Reactant: N#C[S-]
Reactant: COc1ccc(N)cc1C
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1cc2sc(N)nc2cc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-methoxy-3-methylbenzenamine (1.05 g, 7.66 mmol) in acetic acid (30 ml) at 0° C. as added KSCN with heavy stirring. The reaction mixture was then stirred at room temperature for 45 min. The reaction was cooled to 0° C. and bromine was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected, washed by acetic acid, dichloromethane, minimal water and dried under high vacuum to give the product as brown yellow solid. LCMS-ESI+: calc'd for C9H10N2OS: 195.0 (M+H+). Found: 195.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]([CH3:45])[C:37]4=[O:46])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O>[CH3:45][N:38]1[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[N:36]([CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][N:14]3[C:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]=4[C:16]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)=[N:15]3)[CH2:31][CH2:32]2)[C:37]1=[O:46]
Reactant: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(C(=O)OC(C)(C)C)C4)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCNC4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.19 g, 1.86 mmol) was dissolved in trifluoroacetic acid (5 mL) and CH2Cl2 (5 mL) and allowed to stir at room temperature for 2 h. The reaction mixture was concentrated, diluted with CH2Cl2, and washed with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to afford 1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one (0.955 g, 96%) as a white foam. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.19. MS (electrospray) calculated for C29H33F3N6O, 539.3 ([M+H]+). m/z found, 539.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([NH2:14])[N:3]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2ccccc2)n1

Procedure:
Following the method described in Example 53, 4-chloro-6-phenyl-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound as the hydrochloride salt (63% yield). 1H NMR (DMSO-d6) δ 6.70 (s, 1H, Ar), 7.47 (d, 2H, J=8.7 Hz, Ar), 7.66 (d, 3H, J=6.9 Hz, Ar), 7.88 (d, 4H, J=7.2 Hz, Ar), 9.42 (s, 1H, NH), 12.91 (s, 1H, NH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:42])[CH2:39][CH2:40][CH3:41].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C(C)C)COC1>ClCCl.CO>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][NH:1][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: CCCC(=O)Cl
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)C(C)C)COC2)c1OC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added diisopropylethylamine (50 mg, 0.390 mmol) and butyryl chloride (41 mg, 0.391 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 193 and purification by column chromatography (silica gel, 0-3% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: CO[Na].[N:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[C:5]=[S:6].[NH2:15][C:16]#[N:17].Cl[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CO>[CH3:23][O:22][C:20]([C:19]1[S:6][C:5]([NH:4][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:17][C:16]=1[NH2:15])=[O:21]
Reactant: N#CN
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: COC(=O)CCl
Agent: CO[Na]
Solvent: CO
Product: COC(=O)c1sc(Nc2ccc(C#N)cc2)nc1N
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A solution of MeONa in methanol (25% by wt., 2.0 mL, 9.36 mmol) was added dropwise to a suspension of 4-isothiocyanato-benzonitrile Compound 4a (1.0 g, 6.24 mmol) and NH2CN (0.289 g, 6.87 mmol) in methanol (25 mL) at 0° C. The mixture was stirred at r.t. until Compound 4a was no longer detected (about 3 hrs). Methyl chloroacetate (0.657 mL, 7.49 mmol) was added at r.t. and the mixture was stirred at 50-60° C. for 3 hrs, then at r.t. overnight. The mixture was evaporated to dryness in vacuo, then the residual solid was thoroughly washed with water, methylene chloride and a small amount of methanol to give 4-amino-2-(4-cyano-phenylamino)-thiazole-5-carboxylic acid methyl ester Compound 4b (1.06 g, 62%) as a yellow powder. MS 273 (M−H+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH3:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([Cl:14])[CH3:10])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(O)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(Cl)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (±)-1-(2,4-dichloro-pyrimidin-5-yl)-ethanol (1.27 g, 6.60 mmol) (from Example 1a supra) in phosphorus oxychloride (5.0 mL, 53.11 mmol) (Aldrich), at 0° C., was added diisopropylethyl-amine (2.60 mL, 14.78 mmol) (Aldrich). The reaction was stirred at 0° C. for 5 minutes, at ambient temperature for 15 minutes and then at 115° C. for 3 hours. The reaction was cooled to room temperature, diluted with toluene (10 mL) and the mixture was then poured into ice (15 g). After stirring for 10 minutes, the layers were separated and the aqueous extract was back washed with toluene. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (Biotage, 40M, 10:90 to 15:85 ethyl acetate-hexanes gradient) gave (±)-2,4-dichloro-5-(1-chloroethyl)-pyrimidine as an oil. (Yield 1.233 g; 88.3%).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28]N1C(=O)CCC1=O>ClCCl>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:17]([CH2:20][CH3:21])=[CH:18][C:19]=1[Br:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(OCc2ccccc2)cc1OCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCC#N
Reaction time: 5.5 h
Yield: 47.4 %

Procedure:
Carbon tetrachloride (30 mL) was used to dissolve 4-(Benzyloxy)-2-[(3-cyanopropyl)oxy]-1-ethylbenzene (2.5 g). N-bromosuccinimide (1.66 g) was added to the solution and it was stirred for 5.5 hours. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was crystallized from hexane/ethyl acetate at −20° C. to afford 1-(benzyloxy)-2-bromo-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene as a white crystalline solid (1.5 g). NMR (CDCl3) 1.14, t (3H); 2.14, m (2H); 2.55, m (4H); 3.98, t (2H); 5.12, s (2H); 6.45, s (1H); 7.37, m (6H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(CBr)cn1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.59 g, 2.07 mmol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (0.62 g, 2.4 mmol) in THF (15 mL) was added NaH (0.06 g, 2.4 mmol). The reaction stirred at 60° C. for 3.5 hours. The solvent was removed under reduced pressure and the residue was partitioned over dichloromethane and citric acid (5%). The organic extracts were washed with water and dried over Na2SO4 (anhydrous). The organic extracts were concentrated and the residue was purified by flash column chromatography (100% ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to remove solvent. 1H NMR (CD3OD, 400 MHz) δ 9.11 (d, 1H, J=1.6 Hz), 8.77 (s, 1H), 7.52 (m, 1H), 7.02 (m, 2H), 6.57 (s, 1H), 5.53 (s, 2H), 5.30 (s, 2H), 4.49 (q, 2H), 2.52 (s, 3H), 1.39 (t, 3H, J=7.2 Hz); ES-HRMS m/z 450.1045 (M+H calculated for C21H19N3O4ClF2 requires 450.01027).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[H][H]>C(O)C.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
The crude Boc-Asn-Leu-Gly-OBzl was suspended in 2.0 l 50% ethanol. Addition of 10 g 10% Palladium on carbon and hydrogenation for one hour at 3 bar hydrogen pressure under stirring. The crude solution was filtrated and pH adjusted to 3.0 with a 1N sodium hydrochloric acid solution. Removal of ethanol under vacuum at 40° C. resulted in crystallisation of product. Filtration and drying under vacuum at 40° C. for 2 days gave the pure product. Yield 72.3 g (58%).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[O:10][CH2:11][CH2:12][OH:13].C>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: COc1ccccc1OCCO
Reactant: NS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1OCCOS(N)(=O)=O

Procedure:
The title compound was prepared by the procedure of Example 16 from sulfamoyl chloride and 2-(2-methoxyphenoxy)ethanol. The solid obtained was dissolved in 150 ml of methylene chloride, and the solution was treated with charcoal and filtered through Celite®. The filtrate was evaporated under reduced pressure and the solid residue was recrystallized from methylene chloride-petroleum ether (30°-60° C.) to give the title compound in 25% yield as a white solid, mp 102°-104° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([C@H:23]4[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:27][CH2:28]4)[CH:22]=2)=[CH:3][C:2]([C:42]2[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1

Procedure:
Following general procedure M, tert-butyl (trans-4-(4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)carbamate (45 mg, 0.081 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) to afford the desired product (23 mg, 45%) as a yellow-brown solid. ESI MS m/z 636 [C33H35Cl2N5O4+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.[NH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29]([NH:32][O:33][CH:34]5[CH2:39][CH2:38][CH2:37][CH2:36][O:35]5)=[O:30])[CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NOC1CCCCO1
Reactant: COc1cccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)c1
Solvent: ClCCl
Product: COc1cccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c1

Procedure:
(E)-3-{1′-[2-(3-Methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (165 mg, 0.360 mmol) was suspended in DCM (5 ml). TEA (0.075 ml, 0.54 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(3-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving a light yellow solid (103 mg, hydrochloride salt).
Reaction SMILES: S([O-])([O-])(=O)=O.[NH4+:6].[NH4+:7].N.[NH4+].[OH-:10].O=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])O)O)O)O>[O-]S([O-])(=O)=O.[Mn+2].O>[NH2:6][C@H:19]([C:21]([OH:22])=[O:10])[CH2:17][CH2:15][CH2:13][CH2:12][NH2:7]
Reactant: [NH4+]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: [Mn+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Production stage medium was composed of 40 g/l (db) corn steep liquor, 20 g/l ammonium sulfate as raffinate, 12.0 mg/l MnSO4—H2O, 0.75 mls/l antifoam and 12 g/l dextrose, sterilized separately as a 250 g/l solution and added just prior to inoculation. Media formulation was based on a 2.1 liter initial volume which includes 500 mls of mature second stage broth as inoculum. Operating parameters were the following: 32° C., 2.1 vvm air, and an initial and control point pH of 7.2. pH control was again done with NH3 or NH4OH. Agitation was initially 600 rpm, increased to 700 rpm at 9 hrs culture time and 900 rpm at 19 hrs culture time. The fermentation was fed on demand, as indicated by pH increases due to dextrose depletion, a mixture of dextrose and ammonium sulfate. The feed was prepared by sterilizing separately 2310 g dextrose +800 mls water and a volume of raffinate containing a total of 176 g of ammonium sulfate, then combining the two solutions upon cooling to ambient temperature. Total fermentation time was 48 hrs. The vessel size was the same as that used for the second stage inoculum development.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[C:19]([F:31])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:32]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:32])[C:24]4=[O:30])=[C:19]([F:31])[CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)c(F)c3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-2-fluorophenyl}-5-methylimidazolidine-2,4-dione (90 mg) described in Example 528 and methyl iodide (17 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (22 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[O:18][CH3:19])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24]Br)[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:24][CH:23]([CH2:26][CH3:27])[CH2:21][CH3:22])=[CH:13][C:12]=1[O:18][CH3:19])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)CBr
Reactant: COc1cc(O)ccc1[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)c(OC)c1
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To 34 mg (0.122 mmol) of the [(R)-2-hydroxy-1-(4-hydroxy-2-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester and 2-ethylbutylbromide (20 ul, 0.182 mmol) dissolved in 1 ml DMF was added K2CO3 (34 mg, 0.244 mmol) and heated to 60° C. overnight. It was cooled to rt, diluted with ether, and quenched with water. The organic layer was washed with water and brine, and then dried over MgSO4. After removal of the solvent, the residue was purified by flash column (35% EtOAc in hexane) to give the titled compound (24 mg, 54%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][N:5]2[N:9]=[CH:10][C:11]([CH2:12][CH2:13]C(O)=O)=[C:4]12)=[O:2].C([N:19](CC)CC)C.Cl[C:25]([O:27][CH2:28]C)=[O:26].[N-]=[N+]=[N-].[Na+]>O.C(Cl)Cl.O1CCCC1>[CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][N:5]2[N:9]=[CH:10][C:11]([CH2:12][CH2:13][NH:19][C:25](=[O:26])[O:27][CH3:28])=[C:4]12)=[O:2]
Reactant: CCOC(=O)Cl
Reactant: O=CN1CCCn2ncc(CCC(=O)O)c21
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NCCc1cnn2c1N(C=O)CCC2

Procedure:
To a mixture of 3-(4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionic acid (18.0 g), triethylamine (9.8 g) and tetrahyrofuran (300 ml) was added dropwise ethyl chloroformate (9.6 g) under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture was added a solution of sodium azide (6.68 g) in water (100 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methylene chloride, and the aqueous layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. To the oily residue was added methanol (100 ml), and the mixture was stirred under reflux for 1.5 hours. The reaction mixture was concentrated in vacuo to give crude methyl N-[2-(4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)ethyl]carbamate as an oil. This product was used in the next step without further purification.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7](O)[C:6]([NH2:10])=[C:5](O)[N:4]=1.[Cl-:12].C([N+]1(C)CCCCC1)C.P(Cl)(Cl)(Cl)=O>>[NH2:2][C:3]1[N:8]=[C:7]([Cl:1])[C:6]([NH2:10])=[C:5]([Cl:12])[N:4]=1
Reactant: [Cl-]
Reactant: Nc1nc(O)c(N)c(O)n1
Reactant: Cl
Agent: CC[N+]1(C)CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c(N)c(Cl)n1
Reaction time: 24 h
Yield: 62.9 %

Procedure:
Dry 2,5-Diamino-4,6-dihydroxypyrimidine hydrochloride (3.6 g), dry N-ethyl-N-methyl piperidinium chloride (22 g) and phosphorus oxychloride (13 ml) were heated at 105° with stirring for 24 hours. The reaction mixture was processed as in Example 1 to give 2.27 g (65% yield) of 2,5-diamino-4,6-dichloropyrimidine.
Reaction SMILES: CC1C=C2C(=CC=1C)C(=O)CC2.[Br:13]C1CC2C(=CC(C)=C(C)C=2)C1=O.C(N)(=S)C.Br.[CH3:31][C:32]1[S:33][CH:34]2[CH2:43][C:42]3[CH:41]=[C:40]([CH3:44])[C:39]([CH3:45])=[CH:38][C:37]=3[C:35]2(O)[N:36]=1>CC(C)=O.C(O)(=O)C>[BrH:13].[CH3:31][C:32]1[S:33][C:34]2[CH2:43][C:42]3[CH:41]=[C:40]([CH3:44])[C:39]([CH3:45])=[CH:38][C:37]=3[C:35]=2[N:36]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(Br)C2
Reactant: CC1=NC2(O)c3cc(C)c(C)cc3CC2S1
Agent: Br
Agent: CC(N)=S
Agent: Cc1cc2c(cc1C)C(=O)CC2
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c(s1)Cc1cc(C)c(C)cc1-2

Procedure:
5,6-Dimethylindan-1-one is converted as described above for the other indan-1-ones into 2-bromo-5,6-dimethylindan-1-one. This is reacted with an equivalent amount of thioacetamide in acetone. The precipitate consisting of the hydrobromide of 2,5,6-trimethyl-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol is heated in glacial acetic acid and affords, after removal of the solvent and treatment with diisopropyl ether, 2,5,6-trimethyl-8H-indeno[1,2-d]thiazole hydrobromide with a melting point of 290° C.