Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH2:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].Cl.[O-:25][C:26]#[N:27].[K+]>C(O)C.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH:20][C:26]([NH2:27])=[O:25])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: N#C[O-]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3N
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3NC(N)=O
Yield: 57.1 %

Procedure:
To a solution of 4-amino-1,8-diethyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetic acid methyl ester 12 (prepared in Example 1) (1.10 g, 3.48 mmol) in ethanol (20 mL), stirred at room temperature under nitrogen, was added aqueous 1N HCl (6.96 mL) followed by potassium cyanate (0.565 g, 6.96 mmol) dissolved in a little water. After 2 hours the ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Drying (MgSO4) and flash chromatography (1% MeOH in EtOAc eluent) afforded the product (0.714 g, 75%) as a mixture of diastereomers which were separated by reverse phase chromatography (C18 silica gel; 30% acetonitrile in water). The less polar Isomer A (190 mg) had m.p. 179.5°-180.5° C. (methylene chloride-petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[H][H]>CO.Cl.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2([OH:18])[CH2:14][CH2:15][CH2:16][CH2:17]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19]
Reactant: [H][H]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(CCC3(O)CCCC3)nc21

Procedure:
To a solution of 300 mg of 1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1-cyclopentanol in 20 ml of methanol were added six drops of 5N hydrochloric acid and 63 mg of 10% palladium/carbon and the mixture was stirred in a hydrogen atmosphere at room temperature for 17 hours. The palladium/carbon was filtered off, the filtrate was concentrated and the residue was dissolved in ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was subjected to a silica gel column chromatography (15 g of silica gel; dichloromethane, dichloromethane/methanol (40:1, 20:1 and 10:1) to give 1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclopentanol. This was dissolved in methanol and then five drops of 5N hydrochloric acid were added thereto followed by concentrating. Ether was added to the residue and the crystals were collected by filtration and washed with ether to give 6209 mg of the product. The yield was 69%.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7]2OC(=O)[S:9][N:8]=2)[CH2:3]1.ClC1C=CC=C(Cl)C=1.[F:22][C:23]([F:32])([F:31])[C:24]#[C:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:23]([F:31])([F:32])[F:22])[S:9][N:8]=2)[CH2:3]1
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: O=c1oc(C2CCC(F)(F)C2)ns1
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(C2CCC(F)(F)C2)nsc1C(F)(F)F
Temperature: 160 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed 5-(3,3-difluorocyclopentyl)-2H-1,3,4-oxathiazol-2-one (300 mg, 1.45 mmol, 1.00 equiv), 1,3-dichlorobenzene (2 mL), ethyl 4,4,4-trifluorobut-2-ynoate (481 mg, 2.90 mmol, 2.00 equiv). The resulting solution was stirred overnight at 160° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/30). This resulted in 200 mg of ethyl 3-(3,3-difluorocyclopentyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate as brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C([O-])(O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[N:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(F)cn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
To a 0° C. solution of 2-amino-5-fluoropyridine (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89 mmol). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5%→40% EtOAc/hexanes) to give the title compound (1.34 g). MS: m/z=197.3 (M+1).
Reaction SMILES: [OH-].C[Sn+](C)C.[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:23])[N:15]2[CH2:18][C:19]([O:21]C)=[O:20])=[CH:10][CH:9]=1)#[N:7]>ClCCCl.ClCCl>[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:23])[N:15]2[CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1)#[N:7]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(C#N)cc21
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1ccc2ccc(=O)n(CC(=O)O)c2c1
Yield: 88.9 %

Procedure:
Trimethyl tin hydroxide (0.388 g, 2.14 mmol) was added to a solution of methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.104 g, 0.429 mmol) in 1,2-dichloroethane (5 mL) and the resulting suspension was stirred at reflux for 4 h. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous HCl. Filtration of the organic phase provided 87 mg (89%) of 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetic acid. Retention time (min)=0.987, method [1], MS(ESI) 229.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[I:13]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of ethyl 4-aminobenzoate (13.0 g) in DMF (33 mL) is added a solution of N-iodosuccinimide (18.6 g) in DMF (39 mL). The reaction is stirred at room temperature overnight. The mixture is poured into 800 mL water. The resulting solid is collected and dried to yield 20.7 g (90%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].N1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:16]([C:17]1[CH:2]=[C:3]([CH3:4])[C:7]([O:13][CH3:14])=[C:19]([CH3:20])[CH:18]=1)=[N:1]2
Reactant: c1ccncc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OC)c(C)c3)nc2c1
Reaction time: 16 h
Yield: 158.8 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzamide (0.0990 g, 0.555 mmol) and pyridine (44.9 μL, 0.555 mmol) in THF (2.02 mL) was added dropwise a solution of the acid chloride (crude residue described above) in THF (925 μL). After 16 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (3×75 mL), saturated aqueous NaHCO3 (3×75 mL), and brine (75 mL). The insoluble yellow solid was isolated by filtration to provide the amide (0.150 g, 83%). A mixture of the amide (0.148 g, 0.413 mmol) and 2 M NaOH (7.00 mL) was heated at 85° C. for 19 h, cooled to 5° C., and neutralized with 4 M HCl in dioxanes. The white solid was filtered and rinsed with acetone to provide 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.144 g, 100%). Selected data: 1H NMR (300 MHz, CDCl3) δ 11.00 (s, 1H), 7.90 (s, 2H), 6.74 (d, J=2.33 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H), 2.29 (s, 6H); MS (APCI) m/z 341 [M+H]+.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:34][C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35](=[O:41])[C@H:36]([CH:38]([CH3:39])[CH3:40])[NH:37][C:6](=[O:8])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
Boc-Val-OH (2.86 g, 13.2 mmol) was coupled to valine benzyl ester p-toluenesulfonate (5.0 g, 13.2 mmol) using the procedure of Example 55 to give 5.41g, (100%) of the desired product (RF 0.15; 20% ethyl acetate in hexane) as a colorless gum. Mass spectrum M+H)+ =407.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:45]([CH3:46])=[CH:44][C:39]([O:40][CH2:41][C:42]#[N:43])=[CH:38][C:37]=1[CH3:47]>>[C:42]([CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:47])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:45]([CH3:46])[CH:44]=1)#[N:43]
Reactant: Cc1cc(OCC#N)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC#N)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(4-bromo-3,5-dimethylphenoxy)acetonitrile following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.71 min; Mass spectrum (ESI+): m/z=502 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:27][NH2:28]>O1CCOCC1>[NH:27]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:28]
Reactant: COc1cc(C(=O)N2CCc3nnc(Cl)cc3C2)cc(OC)c1OC
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCc3nnc(NN)cc3C2)cc(OC)c1OC

Procedure:
12.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(3,4,5-trimethoxybenzoyl)pyrido[4,3-c]pyridazine and 40 cc of hydrazine hydrate in 40 cc of dioxane are stirred at a bath temperature of 100° for 41/2 hours. The title compound has a M.P. of 194°- 197° (decomp., from absolute ethanol/methanol 2:1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 4-fluoro-1H-indole-7-carboxylic acid and 80 mg (0.3 mmol) of (4-tert-butyl-benzyl)-2-phenyl-ethyl-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 105 mg (72%) product as a white solid. MS (ISP) 429.6 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:8]1[C:7]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)([OH:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Cc1cccc(C2(O)C(=O)Nc3ccccc32)c1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cccc(C2(O)C(NCCCO)=Nc3ccccc32)c1

Procedure:
Reaction of 3-aminopropanol with 3-hydroxy-3-(m-tolyl)-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 2-(3-hydroxypropylamino)-3-(m-tolyl)-3H-indol-3-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:48][C:49]1[CH:73]=[C:72](O)[CH:71]=[CH:70][C:50]=1[C:51]([NH:53][C:54]1[CH:63]=[C:62]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:61]=[CH:60][C:55]=1[C:56]([O:58][CH3:59])=[O:57])=[O:52]>O1CCCC1>[OH:48][C:49]1[CH:73]=[C:72]([CH:71]=[CH:70][C:50]=1[C:51](=[O:52])[NH:53][C:54]1[CH:63]=[C:62]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:61]=[CH:60][C:55]=1[C:56]([O:58][CH3:59])=[O:57])[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (0.15 g), triphenylphosphine (0.21 g), and diisopropyl azodicarboxylate (0.16 mL) were added to a tetrahydrofuran (3.6 mL) suspension of methyl 2-(2,4-dihydroxybenzamido)-4-phenylbenzoate (0.24 g), followed by stirring at room temperature for 1 hour. 1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (0.066 g), triphenylphosphine (0.086 g), and diisopropyl azodicarboxylate (0.064 mL) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 100-75% hexane/ethyl acetate] to obtain 0.050 g of tert-butyl 4-(3-hydroxy-4-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)phenoxy)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.CC[N:19]([CH:23]([CH3:25])[CH3:24])C(C)C.C1(N)CC1>O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:23]1[CH2:25][CH2:24]1)=[O:6]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(I)cccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To 2-amino-3-iodo-benzoic acid (200 mg, 0.76 mmol) in DMF (1 mL) TBTU (244.15 mg, 0.76 mmol) and DIPEA (245.69 μL, 1.52 mmol) are added and stirred at r.t. for 7 min. Cyclopropylamine (52.69 μL, 0.76 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with water and the precipitate is filtered off and dried.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])=[C:23]([F:28])[CH:22]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2c(OC)c1OC
Yield: 67.2 %

Procedure:
A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.177 g of 4-chloro-2-fluoroaniline, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was extracted with ethyl acetate, washed with water, dried and concentrated in vacuo. The solid thus obtained was chromatographed on silica gel eluting with hexanes-ethyl acetate 9:1 to 2:1. Solvent was removed from product fractions giving 0.261 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a yellow solid: mp 166-168° C.; mass spectrum (EI, m/e): M 387.0777.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]1C[O:11]1.[C:13]([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:13])[CH:10]=[O:11]
Reactant: O=C([O-])O
Reactant: Cc1cccc(CC2CO2)c1C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C(C)C=O)c1C
Reaction time: 2 h

Procedure:
2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), prepared according to example 1 (158 mg, 0.97 mmol), was dissolved in toluene (1.57 mL) and BF3OEt2 (0.006 ml, 0.05 mmol) was added at room temperature. After 2 h at room temperature, a sample was mixed with solid NaHCO3, filtered, concentrated under reduced pressure, and the residue was analyzed by 1H NMR. The crude product consisted essentially of pure 2-(2,3-dimethylphenyl)propanal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:18][CH:17]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(-c2nc(COc3ccccc3)co2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(COc3ccc(S(=O)(=O)Cl)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
950 mg 2-(4-Methoxy-phenyl)-4-phenoxymethyl-oxazole were dissolved in 9 ml dichloromethane. At −20° C. 0.90 ml chlorosulfonic acid were added dropwise. The cooling bath was removed and the reaction mixture stirred at room temperature for two hours. The reaction mixture was cooled to 0° C., then 20 ml ice water were added and the reaction mixture extracted five times with portions of 50 ml dichloromethane. The combined organic layers were washed with water and then dried over MgSO4. The solvent was then removed in vacuo to obtain 580 mg 4-[2-(4-Methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl chloride.
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13](=[O:20])[C:12]=2[C:11]([CH3:21])=[N:10]1.C1CCCCC1>C(O)C>[OH:20][CH:13]1[CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][C:17]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)[N:10]=[C:11]([CH3:21])[C:12]1=2
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCCCC1
Product: Cc1nn(-c2ccccn2)c2c1C(O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
0.09 g (2.36 mol) of sodium borohydride were added portionwise to the solution of 1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.3 g, 1.18 mmol), prepared as described in example 3, in ethanol (15 ml) maintained under inert atmosphere and under magnetic stirring at room temperature. After about 20 hours, additional sodium borohydride (0.09 g) was added and the reaction mixture was heated at about 50° C. for about 8 hours. The solvent was evaporated and the residue was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give a foam which was treated with cyclohexane and filtered to yield the title compound as a colourless solid (0.2 g, 66%): m.p. 125-126° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[C:8]([CH2:11][N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1.Cl[C:22]1[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=1>C1COCC1>[Cl:10][C:9]1[C:4]([NH:3][C:22]2[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=2)=[N:5][CH:6]=[CH:7][C:8]=1[CH2:11][N:12]1[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[CH2:14][CH2:13]1
Reactant: CN1CCN(Cc2ccnc(N)c2Cl)CCC1=O
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2Cl)CCC1=O
Temperature: 25 °C

Procedure:
NaH (0.016 g, 0.40 mmol) was stirred in anhydrous THF, 1.5 mL, under N2. 1-(2-Amino-3-chloro-pyridin-4-ylmethyl)-4-methyl-[1,4]diazepan-5-one (0.045 g, 0.17 mmol) was added followed after 10 min by the addition of 2-chloro-thiazole-5-carbonitrile (0.034 g, 0.23 mmol) and the reaction was heated to reflux. After 4 h the reaction was cooled to RT and quenched by the addition of water. The pH was adjusted to 7 with 1M HCl and the mixture was extracted 3× with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC to afford a colorless oil. The residue was azeotroped 3× with MeOH and the resulting residue was dissolved in a minimum of MeOH. The solvent slowly evaporated to afford a white solid which was further dried in vacuo. TFA salt: 1H NMR (CD3OD) δ8.46 (d, 1H, J=5.1 Hz), 8.12 (s, 1H), 7.34 (d, 1H, J=5.1 Hz), 4.43 (s, 2H), 3.75 (m, 2H), 3.36 (m, 4H), 3.02 (s, 3H), 2.88 (m, 2H). MS [M+H]+=377.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=O)[CH3:7])[CH3:2].[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH:6]([NH:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C(C)NC1CCCC1
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a solution of 2.1 g (0.014 mole) of 2-methyl-3-oxo-butanoic acid ethyl ester and 40 mL of dichloroethane was added 1.37 g (0.016 mole) of cyclopentylamine. The mixture was stirred for 1.5 hours, then 4.63 g (0.020 mole) of sodium triacetoxyborohydride and 0.84 g (0.014 mole) of acetic acid were added. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of 50 mL of saturated aqueous sodium bicarbonate. After 20 minutes, the organic layer was separated and the aqueous layer was extracted twice with 30 mL of dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the crude product as yellow oil. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (30:70) gave 1.5 g of (rac)-3-cyclopentylamino-2-methyl-butanoic acid ethyl ester.