Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([O:27][CH3:28])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@@H:18]([CH2:20][N:21]=[N+]=[N-])[O:17][C:16]3=[O:24])=[CH:11][CH:10]=2)[CH2:5][C:4]1([F:26])[F:25]>[Pd].C(OCC)(=O)C>[CH3:28][O:27][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH2:21])[O:17][C:16]3=[O:24])=[CH:11][CH:10]=2)[CH2:5][C:4]1([F:26])[F:25]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1(OC)CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2)CC1(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 88 %

Procedure:
The suspension of (S)-{3-[4-(4,4-dimethoxy-3,3-difluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-azide (10 mmol) and 10% palladium on carbon (0.15 g) was in ethyl acetate was stirred at a room temperature under hydrogen atmosphere for 10 hours. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified on silica gel column chromatography to provide title compound in 88% yield.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]1[CH2:28][O:27][C:13]2([CH2:18][CH2:17][N:16]([C:19]3[N:24]=[C:23]([Cl:25])[CH:22]=[C:21](Cl)[N:20]=3)[CH2:15][CH2:14]2)[O:12]1>C(O)CCC>[CH2:28]1[CH2:11][O:12][C:13]2([CH2:14][CH2:15][N:16]([C:19]3[N:20]=[C:21]([N:8]4[CH2:9][CH2:10][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)[CH:22]=[C:23]([Cl:25])[N:24]=3)[CH2:17][CH2:18]2)[O:27]1
Reactant: Clc1cc(Cl)nc(N2CCC3(CC2)OCCO3)n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCCCO
Product: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCC3(CC2)OCCO3)n1

Procedure:
After adding 2.6 ml (17.23 mmoles) of 1,4-dioxa-8-azaspiro[4,5]decane to the solution of 2.0 g (6.89 mmoles) of 2-(4,4-ethylenedioxy-1-piperidinyl)-4,6-dichloropyrimidine in 40 ml of n-butanol, the reaction mixture is boiled under reflux for 4 hours, then evaporated. The evaporation residue is distributed between 50 ml of chloroform and 5 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 10 ml of water each, then dried and evaporated. After recrystallizing the obtained product from hexane the title compound is obtained in a yield of 2.51 g (91%), m.p.: 130°-131° C.
Reaction SMILES: [CH2:1]([C:5]1([N:23]([CH3:25])[CH3:24])[CH2:10][CH2:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=3)=[CH:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]>Br.CCO>[CH2:1]([C:5]1([N:23]([CH3:24])[CH3:25])[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(N(C)C)CC=C(c2[nH]c3ccc(OC)cc3c2C)CC1
Agent: Br
Solvent: CCO
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccc(OC)cc3c2C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(±)-N-[1-Butyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)cyclohex-3-enyl]-N,N-dimethylamine (1.5 g, 4.4 mmol) was suspended in HBr/glacial acetic acid (33% HBr, 20 ml). Sn powder (2.6 g, 22 mmol) was then added to the mixture in portions at RT in the course of 30 min. When the addition had ended, the reaction mixture was stirred at RT for a further 24 h.—For working up, the mixture was diluted with EtOH (20 ml) and concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 5 N NaOH (100 ml). The aqueous mixture obtained was extracted with methylene chloride (4×20 ml). The combined organic phases were washed with water (50 ml), dried over Na2SO4 and then concentrated. The residue obtained (1.5 g) was purified by column chromatography [silica gel 60 (70 g); EtOAc (400 ml), methanol (400 ml)]. 1-Butyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)-N,N-dimethylcyclohexanamine (less polar diastereomer) was obtained in a yield of 141 mg (10%) as a brown oil. The more polar product had to be purified by a second column chromatography [silica gel 60 (50 g); methanol (200 ml), MeCN/methanol/1 M NH4Cl soln. 9:1:1, (250 ml)]. It was obtained in a yield of 125 mg (8%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.N1CCOC[C@H]1C(O)=O>CO>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: O=C(O)[C@@H]1COCCN1
Solvent: CO
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2

Procedure:
An enantiomeric mixture of 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 8 g) was dissolved in MeOH (400 mL) and was separated by supercritical fluid chromatography (SFC) (Chiralcel® AS-H (5 μm, 20×150 mm), 20% MeOH in liquid CO2 at 55 mL/min, 3 mL/injection). The peak eluting at ˜5 minutes was collected. The stereo-configuration was assigned based on a comparison of retention times of an enantiomerically-enriched sample synthesized in a manner similar to PREPARATION x1 and PREPARATION x2 using optically pure (S)-morpholine-3-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:23])[CH:3]=1
Reactant: Cc1c(Cn2cnc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1c(Cn2cnc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 4-bromo-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (2.5 g, 6.04 mmol) in Methanol (30 mL) in a 250 ml round bottomed flask was added Tin(II)chloride dihydrate (8.17 g, 36.2 mmol) and HCl (1.65 mL, 54.3 mmol). The reaction mixture was left to stir at 80° C. for 1 h. The solvent was removed and diluted with water (100 mL) and this solution was decanted into a 250 mL Erlenmeyer flask. The brown residue in the round bottomed flask was dissolved in 100 mL of EtOAc and washed with 1N NaOH, brine, dried and evaporated to yield a brown solid. The water layer was extracted with EtOAc, washed with 1N NaOH, brine, dried (MgSO4) and evaporated to a brown solid. The solids found to be identical by 1 cms and were combined to yield 4-bromo-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (2.28 g, 5.93 mmol, 98% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44 (s, 3H) 5.24 (s, 2H) 6.39 (d, J=2.02 Hz, 1H) 6.87 (d, J=8.08 Hz, 1H) 6.92 (d, J=2.02 Hz, 1H) 7.21 (t, J=7.83 Hz, 1H) 7.62 (d, J=7.83 Hz, 1H) 7.69 (s, 1H); LC/MS: MS (ES+) m/e 385 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:16][O:17][CH2:18][O:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1>>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:3][C:2]=1[C:21]1[C:20]([O:19][CH2:18][O:17][CH3:16])=[CH:29][C:28]2[C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25][C:24]([CH3:33])([CH3:32])[C:23]=2[CH:22]=1
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Reactant: COCOc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: COCOc1cc2c(cc1-c1cc(C=CC(=O)O)ccc1O)C(C)(C)CCC2(C)C
Yield: 9.9 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 1.6 g (5.5 mmol) of 3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained in Example 13(b), 150 mg (9%) of the expected compound were obtained in the form of a white solid having a melting point of 101°-103° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4](=[O:5])[NH2:6])=[C:2]([OH:1])[CH:10]=1)[CH3:26]
Reactant: NC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(N)=O)c(O)c1
Temperature: 70 °C

Procedure:
To 2,4-dihydroxybenzamide (16.5 g, 108.3 mmol) in DMF (100 mL) was added Cs2CO3 (39.0 g, 119.1 mmol) followed by ethyl 4-bromobutyrate (17.0 mL, 119.1 mmol). The mixture was heated to 70° C. for 2 h, cooled, diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, concentrated, and chomatographed over silica gel (60% EtOAc/hexane) to a white solid (4.2 g, 15%). MS [M+H]− 267.
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].F[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]>CCCCCCC>[OH:2][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]
Reactant: O=C([O-])O
Reactant: CCCCOC(=O)CCCCF
Agent: [Na+]
Solvent: CCCCCCC
Product: CCCCOC(=O)CCCCO
Yield: 92 %

Procedure:
87 mg (0.5 mmol) of butyl 5-hydroxypropionate purified by distillation, 0.39 g (0.6 mmol, 1.2 equivalents) of N,N-diethyl-α,α-difluoro-[4-(1H,1H,2H,2H-perfluorodecyl)benzyl]amine (compound c) produced in Example 1, and 0.5 ml of heptane were put into a PFA container, and reacted in a nitrogen atmosphere at 100° C. for 3 hours. After the reaction, an aqueous saturated sodium hydrogencarbonate solution was added thereto for neutralization, and then the product was extracted out with dichloromethane. The solvent was evaporated away, followed by purification through silica gel column chromatography (solvent: dichloromethane/diethyl ether mixed solvent) to give a product. The main product was butyl 5-fluoropentanoate, and its yield was 92%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[C:25]([S:29][CH2:30][C:31](=O)[CH2:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH3:28])([CH3:27])[CH3:26].O>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:30]([S:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[C:31]2[CH2:32][C:33]([CH3:39])([CH3:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-(4-Chlorobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochloride (50 g; 190 mmol), prepared as in step 1, was dissolved in 400 mL toluene and 220 mL acetic acid. Sodium acetate (17.1 g; 210 mmol) was added followed by the addition of ethyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate (49 g; 188 mmol), prepared as in step 2. The reaction was stirred in the dark at room temperature for 4 days. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water. Solid sodium bicarbonate was added to the organic extracts and the mixture was filtered. The filtrate was washed with water and brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was taken up in hot ethyl acetate and filtered. The solvent was removed and the product was recrystallized from pentane to give ethyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropionate as a fluffy white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(F)c(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,5-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.41-7.56 (m, 2 H), 7.65 (ddd, J=7.9, 5.0, 1.0 Hz, 1 H), 7.98-8.04 (m, 1 H), 8.57 (dt, J=8.0, 1.9 Hz, 1 H), 8.75 (dd, J=5.2, 1.6 Hz, 1 H), 9.31 (dd, J=2.0, 0.8 Hz, 1 H); MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH2:22][C@H:21]1[C:24]([O:26][CH3:27])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C)P(N(C)C)(N(C)C)=O.IC>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH2:22][C:21]1([CH3:1])[C:24]([O:26][CH3:27])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 69.7 %

Procedure:
To a solution of diisopropylamine (1.05 equiv; 5.9 mmol, 0.6 g, 0.83 mL) in anhydrous tetrahydrofuran (15 mL) was added n-butyl lithium (1.05 equiv; 5.9 mmol, 2.36 mL of a 2.5M solution in hexanes) and the resulting light yellow solution was warmed to 0° C. for 10 min. It was then cooled back to −78° C. and N-(tert-butoxycarbonyl)-azetidine-2(S)-carboxylic acid, methyl ester (5.63 mmol, 1.21 g) in dry tetrahydrofuran (3.0 mL) was added dropwise and stirring was continued for 45 min. After this time, hexamethylphosphoramide (2.0 equiv; 11.3 mmol, 2.02 g, 1.96 mL) was added and the reaction mixture was stirred for 0.5 h. At this point, iodomethane (5.0 equiv; 28.2 mmol, 3.99 g, 1.75 mL) was added (−78° C.), the cooling bath was removed, and stirring was continued overnight (16 h) at ambient temperature. Addition of saturated ammonium chloride solution, extraction with ethyl acetate, washing of the combined organic layer with water (2×) and brine, drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes) to provide N-(tert-butyloxycarbonyl)-2(R,S)-methylazetidine-2-carboxylic acid, methyl ester (0.9 g, 70% yield).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.O1CCCCC1OC1CCCCO1.Cl>>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cl
Product: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCO)c3)ccc1-2

Procedure:
Similar to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranyl ether was accomplished by adding 2N HCl to the crude reaction mixture. Purification by reverse phase HPLC gave 403 as a colorless solid (16 mg). LCMS: 438.1
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:18](N(CC)CC)C.S(Cl)(Cl)=O.CO>C1COCC1.CCOC(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc(I)cc2)C1
Reactant: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CN(S(=O)(=O)c2ccc(I)cc2)C1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred solution of 1-[(4-iodophenyl)sulfonyl]azetidine-3-carboxylic acid (0.75 g, 2.06 mmol) in THF (15 mL) is added triethylamine (0.43 mL, 3.09 mmol) followed by thionyl chloride (0.18 mL, 2.47 mmol). After stirring for 1 h, MeOH (10 mL) is added. Stirring is continued for another 1 h. The reaction mixture is concentrated under reduced pressure to give a residue which is taken up in EtOAc and washed with saturated aqueous NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.60 g (77%) of methyl 1-[(4-iodophenyl)sulfonyl]azetidine-3-carboxylate. m/z=382 [M++H].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1
Reactant: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Yield: 88.6 %

Procedure:
A suspension of (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (208 mg, 0.61 mmol) in DCM (7 ml) was treated with TEA (0.14 ml, 1.0 mmol) and then with EDC (196 mg, 1.03 mmol), HOBt (140 mg, 1.03 mmol) and NH2OTHP (97 mg, 0.82 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (217 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[C:16]([C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Reactant: CNC
Product: CCc1cc(-c2ccc(C(=O)N(C)C)o2)c(C)[nH]c1=O
Yield: 50 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-furan-2-carboxylic acid and dimethylamine to afford the title compound (50% yield). LC/MS: RT 2.3 min; m/e 275 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:18])[N:3]=1.[CH:19]1([C:22]2[N:26]=[C:25]([CH2:27][N+:28]#[C-:29])[O:24][N:23]=2)[CH2:21][CH2:20]1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH:19]1([C:22]2[N:26]=[C:25]([C:27]3[N:28]=[CH:29][N:3]4[C:4]5[C:9](=[C:8]([CH3:18])[CH:7]=[CH:6][CH:5]=5)[C:10]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)=[N:11][C:2]=34)[O:24][N:23]=2)[CH2:21][CH2:20]1
Reactant: Cc1cccc2nc(Cl)nc(N3CCOCC3)c12
Reactant: [C-]#[N+]Cc1nc(C2CC2)no1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1c(N1CCOCC1)nc1c(-c3nc(C4CC4)no3)ncn12
Temperature: 0 °C

Procedure:
A mixture of 2-chloro-5-methyl-4-morpholino-quinazoline (1.68 g, 6.4 mmol) and 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole (1.9 g) in 15 ml of dry dimethylformamide was cooled to 0° C. Solid potassium tert-butoxide (1.4 g, 12.5 mmol) was added gradually during 5 min. to the stirred mixture, the temperature being kept below 10° C. The mixture was stirred at ambient temperature for two hors, and then cooled to 0° C. The precipitated crystals were collected by filtration, rinsed on the filter with ethyl acetate and water, and dried to give the title compound as light yellow crystals, m.p. 262°-266° C. Yield 1.29 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1cnc(-c2ccc(F)cc2)o1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cnc(-c2ccc(F)cc2)o1
Yield: 15 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 15%). 1H NMR (400 MHz, MeOD) δ 8.48-8.47 (m, 1H), 8.28-8.25 (m, 1H), 8.00-7.97 (m, 3H), 7.68-7.64 (t, J=7.8 Hz, 1H), 7.21-7.16 (t, J=8.8 Hz, 2H), 7.00 (s, 1H), 3.66 (s, 2H), 1.46 (s, 6H). MS (ESI) m/z: Calculated for C23H18F4N4O3: 474.13. found: 475.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([C:15]1[NH:16][O:17][C:18](=[O:20])[CH:19]=1)[CH2:13][CH3:14]>C(=O)(O)[O-].[Na+]>[CH2:12]([C:15]1[N:16]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[O:17][C:18](=[O:20])[CH:19]=1)[CH2:13][CH3:14]
Reactant: CCCc1cc(=O)o[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1cc(=O)on1C(=O)c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
20.9 gm of 2,4-dichlorobenzoyl chloride was added to 8 gm of 3-n-propyl-3-isoxazolin-5-one. The system was heated at 100° C. for 3 hours. Afterwards, the system was neutralized with 150 ml of saturated sodium bicarbonate solution. The product was extracted with methylene chloride. The organic solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. The organic solution was stripped to yield 28.8 gm of the crude product as a brown oil. The product was purified by HPLC using 1:3 tetrahydrofuran/hexane as the eluant to yield the title compound as a brown solid, m.p. 63°-65.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5]2.[H-].[Na+].I[CH3:23]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([N:12]([CH3:23])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:5]2
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cc2cc(Br)ccc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc2cc(Br)ccc2cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
tert-Butyl 6-bromoisoquinolin-3-ylcarbamate (48 g, 1.5 mmol) was taken up in 10 mL of DMF and chilled to 0° C. Sodium hydride (0.074 g, 1.9 mmol) was added, and the mixture was stirred for 15 minutes. Iodomethane (0.10 mL, 1.6 mmol) was then added, and the mixture was stirred for 30 minutes. The reaction mixture was then quenched with 5 mL of aq NH4Cl. The mixture was then diluted with 50 mL of EtOAc and transferred to a separatory funnel. The mixture was washed five times with 25 mL of water and once with 25 mL of brine. The remaining portion was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0.5% to 7.5% EtOAc/hexanes), affording tert-butyl 6-bromoisoquinolin-3-yl(methyl)carbamate (0.39 g, 78% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.04 (s, 1H) 7.95 (s, 1H) 7.88 (s, 1H) 7.77 (d, J=8.80 Hz, 1H) 7.56 (dd, J=8.61, 1.76 Hz, 1H) 3.48 (s, 3H) 1.57-1.52 (m, 9H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH2:10][CH2:11][F:12]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][CH2:11][F:12])[CH:8]=1
Reactant: Brc1cn[nH]c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCn1cc(Br)cn1
Reaction time: 0.25 h

Procedure:
Sodium hydride (24.22 mg, 0.606 mmol, 60% suspension in mineral oil) was added to a solution of 4-bromo-1H-pyrazole (89 mg, 0.606 mmol) in DMF (3028 μl) at RT. After 15 min, 1-bromo-2-fluoroethane (100 mg, 0.787 mmol) was added to the mixture. After 30 min, the mixture was diluted with DMF and purified by HPLC, followed by neutralization (K2CO3), to afford the title compound as a colorless oil.