Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1.[CH2:32]=O.Cl>C(O)=O>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:5]([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1)[CH3:32]
Reactant: C=O
Reactant: CCCCc1ncc(CN[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: Cl
Solvent: O=CO
Product: CCCCc1ncc(CN(C)[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Yield: 70.4 %

Procedure:
N-[{1-[(2-Chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]phenylalanine methyl ester (prepared in Example 3(i) method B) (o.52 g, 1.18 mmol), 88% formic acid (0.31 g), and 37% aqueous formaldehyde (o.44 g) were heated over a steam bath for 18 hours. The reaction mixture was poured into 10% hydrochloric acid solution and then extracted with diethyl ether. The aqueous layer was basified to pH 10 with 10% sodium hydroxide solution and then the product was extracted into ethyl acetate. The organic extract was dried with anhydrous magnesium sulfate and the solvent was removed in vacuo. The crude product was chromatographed on silica gel with 50% ethyl acetate in hexane to give 0.377 g (70%) of N-[{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol -5-yl}methyl]-N-methylphenylalanine methyl ester. Hydrolysis of the ester following the procedure of Example 2(ii) gave the title compound as a foam (0.265 g, 77%); mp 59°-61° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: CC(C)(CO)CBr
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Agent: Cl
Product: CC(C)(CO)CN1CCC(c2cc3ccccc3c(=O)[nH]2)CC1
Yield: 15.2 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (510 mg) and 3-bromo-2,2-dimethyl-1-propanol (474 mg), 3-[1-(3-hydroxy-2,2-dimethylpropyl)piperidin-4-yl]-2H-isoquinolin-1-one (92 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:22]([O:24]CC)=[O:23])[CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19]CC)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:22]([OH:24])=[O:23])[CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)CC21CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Add diethyl (1S,2S,5R,6S)-2-(tert-butoxycarbonylamino)spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (1.79 g, 4.87 mmol) in tetrahydrofuran (29.2 mL) to a freshly prepared solution of lithium hydroxide monohydrate (1.64 g, 38.97 mmol) in water (19.5 mL) and stir overnight at 60° C. Dilute with water (30 mL), extract with ethyl acetate (2×50 mL). Separate aqueous and organic layers. Wash organic layer with 2M hydrochloric acid. Wash the aqueous layer with 2M hydrochloric acid (25 mL) then extract with ethyl acetate (2×50 mL). Combine the organic layers and wash with brine (15 mL). Dry on magnesium sulfate, filter and concentrate to dryness. Redissolve in dichloromethane and concentrate to dryness to give the title compound (1.49 g, 98%). MS (m/z): 334 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]>O1CCCC1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][N:16]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Temperature: 10 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
A 3-neck 1 L round-bottom flask equipped with a magnetic stirrer, ice cooling bath, thermometer and an argon inlet tube was set up and charged with 3-chloro-4-(methoxycarbonyl)benzoic acid (Example 72; 21.5 g, 0.1 mol) in tetrahydrofuran (250 mL). The solution was cooled to 10° C. under argon and was treated in succession with N-hydroxysuccinimide (12.66 g, 0.11 mol) and N,N-dicyclohexylcarbodiimide (21.66 g, 0.105 mol). These reagents were washed into the reaction flask with additional tetrahydrofuran (100 mL). A precipitate started to form immediately. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then was diluted with diethyl ether (400 mL) and stirred for another 30 min. The precipitate was collected by filtration and the filter cake was washed with diethyl ether (3×50 mL). The dried solids (N,N-dicyclohexylurea) weighed 22.2 g (>99% of theory). The combined filtrates were diluted with hexane (100 mL) then were transferred to a 2 L separatory funnel and were washed in turn with cold saturated sodium bicarbonate solution (150 mL) and brine (150 mL). Each aqueous layer was back-extracted in turn with diethyl ether (200 mL), then the combined organic extracts were dried (MgSO4) and evaporated to give crude 2-chloro-4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzoic acid methyl ester (˜35 g) as a colorless solid. This material was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:24])([CH3:23])[C:7](=[O:22])[N:8]2[C:11]([NH:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:12])=[CH:4][CH:3]=1.[CH:25]([C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]1)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:24])([CH3:23])[C:7](=[O:22])[N:8]2[C:11]([NH:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][N:18]([CH2:25][C:27]3([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]3)[CH2:17][CH2:16]2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)N(C(=O)NCC2(O)CCNCC2)c2cc(F)ccc21
Reactant: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(O)(CNC(=O)N3C(=O)C(C)(C)c4ccc(F)cc43)CC2)CCC1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 2 from 6-fluoro-N-[(4-hydroxypiperidin-4-yl)methyl]-3,3-dimethyl-2-oxoindoline-1-carboxamide and methyl 1-formylcyclobutanecarboxylate (step 4 of Example 22) and methyl 1-formylcyclobutanecarboxylate (Davis, Charles R. et al., J. Org. Chem., 1993, 58, 6843).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[CH:19]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Similar to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 367. LCMS: 451.1
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1>C(O)C>[F:25][C:10]([F:9])([C:21]([F:23])([F:22])[F:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:2])[CH:14]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cc(OCC(F)(F)C(F)(F)F)ccn1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(OCC(F)(F)C(F)(F)F)ccn1
Reaction time: 6 h
Yield: 101.8 %

Procedure:
To 6 ml of ethanol were added 0.49 g of sodium bicarbonate and 0.4 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.55 g of 4-(2,2,3,3,3-pentafluoropropoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 6 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.6 g of 4-(2,2,3,3,3-pentafluoropropoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=1[CH3:35]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:28]4[C:27]([CH3:35])=[N:26][CH:31]=[CH:30][CH:29]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: Cc1ncccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Agent: Cl
Product: Cc1ncccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 58.9 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-picoline-3-boronic acid hydrochloride salt (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-methyl-pyridin-3-yl)-benzoic acid (65 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.30 (dd, J=7.9, 1.9 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21-7.30 (m, 1H), 2.08 (s, 3H).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([CH2:9][C:10]#[C:11][C:12]#[N:13])[CH2:8][CH2:7][CH2:6][CH2:5]1.CCO>[OH-].[Na+].CCOCC>[CH:4]1([CH2:9][C:10]2[O:3][N:2]=[C:12]([NH2:13])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NO
Reactant: N#CC#CCC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine HCl (20.3 mmol) was dissolved in 14.9 mL of 2.5 M aqueous NaOH solution at rt and 4-Cyclopentyl-but-2-ynenitrile (16.9 mmol) was added in solution with 50 mL EtOH. The cloudy suspension was stirred at rt for 2 hours. The reaction material was then diluted with 200 mL of Et2O and washed with two 50 mL portions of water, followed by 50 mL of aqueous saturated sodium chloride solution. The organics were then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were then purified through flash chromatography to give 5-Cyclopentylmethyl-isoxazol-3-ylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[F:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1F
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 26.4 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (640 mg, 0.003 mol) in N,N-dimethylformamide (7 mL) was added N,N-diisopropylethylamine (2.00 g, 0.015 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (300 mg, 23%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.Cl>C(O)(C)C.O1CCOCC1>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[C:7]3[N:8]([CH3:14])[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: CN1CCNC(=O)c2cccc(N)c21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2N(C)CCNC3=O)ncc1Cl
Temperature: 110 °C
Yield: 6.3 %

Procedure:
9-Amino-1-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (40 mg, 0.21 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (#) (68 mg, 0.23 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (57 μL) was added, and the resulting mixture was heated to 110° C. in the microwave for 20 min. The resulting mixture was filtered, washed with CH2Cl2 and acetone. The ppt was dissolved in H2O, neutralized with NaHCO3, and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-10% MeOH in CH2Cl2) to obtain 2-[5-Chloro-2-(1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (6 mg, 5%). mp 282-284° C.; LCMS: m/z=452.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.30 (s, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.26 (m, 1H), 7.06 (m, 1H), 6.88 (m, 1H), 6.69 (m, 1H), 6.21 (m, 1H), 4.43 (m, 1H), 3.55 (m, 2H), 3.42 (m, 2H), 3.18 (s, 3H), 3.02 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1.O1CCOCC1.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]1
Reactant: Fc1cc(F)c(C2CCC3(CC2)OCCO3)cc1F
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(c2cc(F)c(F)cc2F)CC1

Procedure:
8-(2,4,5-Trifluorophenyl)-1,4-dioxaspiro[4.5]decane was added to a solution of 1,4-dioxane (600 mL), water (160 mL) and concentrated sulfuric acid (160 mL) and the resultant mixture was stirred for one h. The solution was then mixed with water (1 L) and extracted with dichloromethane (1 L). The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to yield the title compound as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:14]=[CH:13][C:12]([I:15])=[CH:11][C:8]=1[C:9]#[N:10]>S(=O)(=O)(O)O.O>[Cl:3][C:7]1[N:14]=[CH:13][C:12]([I:15])=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: N#Cc1cc(I)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1cc(I)cnc1Cl
Temperature: 110 °C
Yield: 389.6 %

Procedure:
30.7 ml (329 mmol) of phosphorus oxychloride at 0° C. and 6 drops of sulfuric acid are added to 9 g (6.6 mmol) of 2-hydroxy-5-iodonicotinonitrile. The reaction mixture is heated at 110° C. for 5 hours and then at room temperature overnight. The reaction mixture is poured in a beaker containing ice and a little water, and a precipitate is formed. The mixture is allowed to gradually return to room temperature and then is filtered and rinsed with water. The solid is dried to yield 6.8 g (70%) of 2-chloro-5-iodonicotinonitrile.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[OH:23][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3cccc(OC)c3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of 7-hydroxy-2-(3-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (129 mg, 0.39 mmole) and glycine (588 mg, 7.83 mmole) in 0.5 M sodium methoxide/methanol (14.8 ml) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (50 ml) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (122 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.48 (br s, 1H), 8.89 (s, 1H), 7.69 (m, 2H), 7.51 (m, 1H), 7.22 (m, 1H). 4.02 (d, J=6.2 Hz, 2H), 3.86 (s, 3H); MS: (+) m/z 359.90 (M+1); (−) m/z 357.92 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[C@H:11]1([NH2:18])[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]1.O1CCCC1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:18])[CH2:12][CH2:13]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)CC1

Procedure:
A solution of 5-nitro-2-chloropyridine (2.50 g) and trans-1,4-cyclohexanediamine (5.40 g) in ethanol (15 ml)-tetrahydrofuran (10 ml) was stirred at room temperature for 5 days. The precipitates were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol-concentrated aqueous ammonia (20:4:1)) and crystallized from ethyl acetate to obtain N-(5-nitro-2-pyridyl)-trans-1,4-cyclohexanediamine (Reference Example 3-1 in Table 5).
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([OH:30])=[CH:28][C:27]([CH2:31][CH:32]4[CH2:34][CH2:33]4)=[CH:26][C:17]=3[O:18][C:19]([CH2:23][CH2:24][CH3:25])([CH2:20][CH2:21][CH3:22])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:35].[N:36]1([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:35].[CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([O:30][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:28][C:27]([CH2:31][CH:32]4[CH2:34][CH2:33]4)=[CH:26][C:17]=3[O:18][C:19]([CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH3:25])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC1(CCC)Oc2cc(CC3CC3)cc(O)c2C2=C1CCN(CC=Cc1ccccc1)C2
Reactant: O=C(O)CCCN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC1(CCC)Oc2cc(CC3CC3)cc(OC(=O)CCCN3CCCC3)c2C2=C1CCN(CC=Cc1ccccc1)C2

Procedure:
2-Cinnamyl-8-cyclopropylmethyl-5,5-di(1-propyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-pyrrolidinobutyric acid hydrochloride and dicyclohexyl-carbodiimide are reacted in equimolar amounts according to Example 1 to form the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Product: Brc1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 147.6 %

Procedure:
In accordance with scheme C-I, 10 g of 2,5-dibromopyridine and 19.24 g of 4-benzyloxyphenylboronic acid are coupled analogously to Example 4a to give 21.2 g (73.9%) of 5-bromo-2-(4-benzyloxyphenyl)pyridine.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[CH3:11][NH2:12]>>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([NH:12][CH3:11])=[O:9]
Reactant: CN
Reactant: O=c1[nH]c2ccccc2o1
Product: CNC(=O)Nc1ccccc1O

Procedure:
Benzoxazolinone (1 mole) was stirred with 2 moles of methylamine (25% aqueous solution) for 48 hours at 50° C., then some of the water and the excess of methylamine were distilled off at 60° C. under reduced pressure. The desired urea crystallised out on cooling; it had m.pt. 130° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccc(F)c(F)c3)c2)SC[C@H]1O

Procedure:
By following a procedure analogous to Example 122 starting from 3,4-difluorophenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(3,4-difluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige powder (yield=44%).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: O
Product: N[C@@H]1CCC[C@@H]1C1CCCCC1
Yield: 33.9 %

Procedure:
Using rhodium-on-charcoal catalyst in a Paar shaker, 12.6 g of cis-2-phenylcyclopentylamine hydrochloride, M.P. 204°-206° C. in 100 ml of water was hydrogenated. In 20 hours when the theoretical amount of hydrogen had been taken up the catalyst was removed by filtration, the filtrate made basic with sodium hydroxide solution, and the resulting precipitate was extracted into ether. After evaporation of the ether the residue was distilled, B.P. 100°-102° C. (6.0 mm). The hydrochloride salt was prepared and recrystallized from isopropanolether to give 4.4 g of cis-2-(cyclohexyl)cyclopentylamine hydrochloride, M.P. 174°-176° C.