Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][N:3]1[C:20](=[O:22])[CH3:21]
Reactant: c1ccc2c(c1)CCCNC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2ccccc2C1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
A suspension of 2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (10 g, 54.4 mmol) in dry dichloromethane (450 mL) was stirred at 0° C. Triethylamine (18.21 mL, 130.6 mmol) was added followed by the dropwise addition of acetic anhydride (6.18 mL, 65.3 mmol) in dry dichloromethane (50 mL). The reaction was then stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The resulting mixture was washed with 1 N hydrochloric acid (200 mL) and brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give 10 g of product as colorless oil (yield was 97%). It was used in next step without further purification. MS obsd. (ESI+) [(M+H)+] 190.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].[C:19]([O-])([O-])=O.[K+].[K+].CI.O>C(#N)C>[CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH3:19])[N:13]=2)=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: CC(C)Oc1ccc(-c2nn(C)cc2C=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)-phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (400 mg, 1.5 mmol) and K2CO3 (624 mg, 4.5 mmol) in acetonitrile (6 mL) was stirred at 0-5° C. for 1 h. Methyl iodide (310 mg, 2.2 mmol) was added and the mixture stirred at ambient temperature for 48 h. The reaction was poured into water (200 mL) and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (100 mL), dried, and concentrated under vacuum. The residue was purified by prep-TLC using Hexane:EtOAc (210:90) as eluent to afford the 3-(4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (82 mg, Yield: 19%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.94 (s, 1H), 8.00 (s, 1H), 7.68-7.64 (m, 2H), 7.02-6.97 (m, 2H), 4.69-4.59 (t, J=6.0 Hz, 1H), 4.00 (s, 3H), 1.38 (d, J=6.0 Hz, 6H) ppm. LCMS (method C RT=2.08 min, m/z=245.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl.[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>CN(C=O)C>[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)CCCCCN
Reactant: Clc1ncnc2oc(-c3ccccc3)cc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)cc12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
Heat 2.0 g (8.67 mmol) 4-chloro-6-phenylfuro[2,3-d]pyrimidine and 6.04 ml (34.7 mmol) DIEA in 5 ml DMF to 160° C. Add 3.15 g (17.34 mmol) 6-aminohexanoic acid methyl ester hydrochloride and stir for 4 h at 160° C. After cooling, add the mixture to ice water and extract three times with ethyl acetate. Combine the organic phases and wash with saturated ammonium chloride solution, dry over magnesium sulphate and concentrate under vacuum. Add methanol to the oil residue. Filter off the precipitated solid with suction, wash with methanol again and dry the solid at high vacuum. 1.85 g (57.2% of theor.) of the target compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:6]([C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccccc2[N+](=O)[O-])c1C

Procedure:
o-Nitroaniline (15 mmol, 2.1 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (15 mmol, 3.7 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over three silica gel columns to yield the named product, 1H-NMR (CDCl3, ppm): 1.36 t (3H), 2.36 s (3H), 4.31 q (2H), 6.80 s (1H), 7.03-7.66 bm (6H), 7.68 dt (2H), 7.97 dd (1H).
Reaction SMILES: COC(=O)[C:4]1[C:9](C)=[CH:8][C:7](C2C=CC=C(C(F)(F)F)C=2)=[N:6][C:5]=1[O:21]C.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.CC1(C)C(C)(C)OB(C2C=CC(O)=NC=2)O1>>[OH:21][C:5]1[N:6]=[CH:7][C:8]([C:25]2[C:26]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=3)=[CH:27][C:28]([CH3:44])=[C:29]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:40][CH2:41][CH2:42][CH2:43]4)[CH2:35][CH2:34]3)=[O:32])[N:30]=2)=[CH:9][CH:4]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Agent: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2ccc(O)nc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol to give the title compound as yellow amorphous solid. MS: 511.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]([NH2:19])=[N:17][CH:18]=2)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH:22]([C:32]1([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][CH:39]=[CH:38]3)[CH2:34][CH2:33]1)[CH:23](N1C(=O)CCC1=O)O>C(O)C>[N:41]1[C:42]2[C:37](=[CH:36][C:35]([C:32]3([C:22]4[N:17]5[CH:18]=[C:13]([C:10]6[CH:11]=[CH:12][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[N:9]=6)[CH:14]=[N:15][C:16]5=[N:19][CH:23]=4)[CH2:34][CH2:33]3)=[CH:44][CH:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cnc(N)nc2)n1
Reactant: O=C1CCC(=O)N1C(O)C(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)n1
Temperature: 105 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of tert-butyl[3-(2-aminopyrimidin-5-yl)-1H-pyrazol-1-yl]acetate (16 mg, 0.058 mmol) and 1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione (20 mg, 0.058 mmol) in ethanol (0.3 mL) was stirred overnight at 105° C. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product (10 mg, 37%). LCMS: (M+H)=467.0.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH2:39]>O1CCCC1.ClCCl>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:33])[NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)O
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCCNC(=O)CCCCCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in a mixture of tetrahydrofuran (5 mL) and dichloromethane (1 mL). The resulting solution was stirred at ambient temperature for 4 h. 3-(Dimethylamino)propylamine (0.10 mL, 0.79 mmol) was then added and stirring continued for 14 hours at room temperature. The solvent was then removed under vacuum. The resulting residue was dissolved in dichloromethane (10 mL) and washed sequentially with aqueous sodium bicarbonate (1×10 mL), and then water (1×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 4 (154 mg, 61%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.57 (br, 14H), 1.56-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.16 (t, 2H, J=7.5 Hz), 2.32 (s, 6H), 2.51 (t, 2H, J=6.7 Hz) 3.29-3.33 (m, 2H), 4.51 (br, 1H); m/z (ESI) 386 [C21H43N3O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:46]=[CH:45][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:37][C@@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1>CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:37][C@@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])=[CH:45][CH:46]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)C)cc2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)C)cc2)cc1
Yield: 93.1 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valine (0.015 g, 0.023 mmol) was dissolved in methanol (3 ml). NABH4 (0.006 g, 0.158 mmol) was added and when the reaction was complete a few drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 25% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.014 g (93%) of the title product was obtained. NMR (500 MHz, CD3COOD) 0.93 (d, 3H), 0.95 (d, 3H), 2.12-2.22 (m, 1H), 2.91-3.07 (m, 2H), 3.75 (s, 1.5H), 3.76 (s, 1.5H), 3.94-4.06 (m, 3H), 4.33 (d, 1H), 4.60 (s, 2H), 4.72-4.78 (m, 1H), 4.81-4.88 (m, 1H), 6.79-6.83 (m, 2H), 6.97-7.08 (m, 4H), 7.20-7.36 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.C(N(C(C)C)C(C)C)C.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1.CO>O1CCCC1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:34]([CH:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)=[O:35])[S:3][C:4]=2[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)C1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCOCC3)nc12
Temperature: 0 °C
Yield: 94.1 %

Procedure:
To a solution of 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.4 mmol) in tetrahydrofurane (2 ml) were subsequently added N-ethyl-diisopropylamine (194 □1, 1.1 mmol) and tetrahydropyran-4-carbonyl chloride (77 mg, 0.52 mmol, dissolved in 0.5 ml tetrahydrofurane) and the mixture refluxed for 3 h. The mixture was then cooled to 0° C., methanol (0.4 ml) was added and the mixture slowly warmed to 20° C. Then the mixture was evaporated to dryness, dichloromethane was added (3 ml) and extracted with saturated aqueous sodium carbonate. After back extraction of the aqueous phase with two portions of dichloromethane (3 ml), the combined organic phases were dryed with Na2SO4 and the solvent evaporated. The crude product was was then chromatographed over SiO2, eluting with CH2Cl2/MeOH 98:2, the product fractions were pooled and the solvent evaporated, to afford the title compound as a beige powder (142 mg, 76% yield), MS: m/e=378(M+H+).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:31][CH2:30]2)=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])CC1
Yield: 93 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzophenone (1.0 eq), 1-Boc-piperazine (1.1 eq), and TEA (2.0 eq) in NMP yielding tert-butyl 4-(4-benzoyl-2-nitrophenyl)piperazine-1-carboxylate (93%). LCMS (m/z): 412.2 (MH+); LC Rt=3.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([NH:28][CH2:29][C:30]#[CH:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][C:30]#[C:31][C:13]1[CH:12]=[N:11][C:7]2[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=3[Cl:1])[C:6]=2[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: C#CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Yield: 63 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was coupled with N-boc propargylamine as in General Procedure 5 to give the title compound as a yellow solid (63% yield). LCMS: m/z=447.49 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.45 (9H, s), 3.41 (2H, t, J=4.8 Hz), 3.62 (2H, s), 4.05 (2H, m), 4.40 (2H, s), 4.81 (1H, m), 5.41 (1H, bs), 6.41 (1H, s), 7.21 (2H, m), 7.34 (1H, d, J=8.3 Hz), 7.61 (1H, s).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:23][O:22][C:21](=[O:24])[N:20]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][C:33]([C:34]4[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=4)=[C:27]3[N:26]=2)=[CH:15][CH:14]=1.OC1C2N=[N:50][NH:49]C=2C=CC=1.O.NN.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:23][O:22][C:21](=[O:24])[N:20]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][C:33]([C:34]4[CH:42]=[CH:41][C:37]([C:38]([NH:49][NH2:50])=[O:40])=[CH:36][CH:35]=4)=[C:27]3[N:26]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.1031 g, 0.5378 mmol) was added to a mixture of (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (0.075 g, 0.1793 mmol) and hydroxybenzotriazole (0.073 g, 0.5378 mmol) in DMF (0.6 mL) at ambient temperature. After stirring for 10 minutes, hydrazine monohydrate (0.02609 mL, 0.5378 mmol), followed by triethylamine (0.07496 mL, 0.5378 mmol) were added. The mixture was stirred at ambient temperature for 4 hours, diluted with EtOAc, washed with aqueous saturated NH4Cl, brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (2-8% MeOH in DCM) to provide (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (0.061 g, 79% yield) as a clear oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH2:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1)[CH:2]=[CH2:3]
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Reactant: C=CCOc1ccccc1OCC1CO1
Product: C=CCOc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3C)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([OH:23])[C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:27]([O:23][CH:12]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2)[C:11]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:26][CH:25]=1)=[O:24])(=[O:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12
Reaction time: 0.5 h

Procedure:
The product from Example 277B (100 mg, 0.287 mmol) and DMAP (59 mg, 0.480 mmol) in CH2Cl2 (1 mL) was treated with acetic anhydride (38 μL). After stirring for 30 minutes, the mixture was treated with CH2Cl2 (5 mL) and the phases separated. The organic layer was washed with water (10 mL×3), dried (Na2SO4), filtered, and the filtrate was concentrated to provide the title compound. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.25 (s, 9H), 4.27 (dq, J1 14.9, J2 6.1, 2H), 6.56 (s, 1H), 7.09 (d, J 8.5, 2H), 7.28 (d, J 8.5, 2H), 7.72 (t, J 7.1, 1H), 7.90 (d, J 6.1, 1H), 8.07 (d, J 6.1, 1H), 8.17 (d, J 8.1, 1H), 8.53 (d, J 6.1, 1H), 8.86 (t, J 6.1, 1H), 9.35 (s, 1H);Anal. Calcd for C24H26N2O3+0.8H2O: C, 71.19; H, 6.87; N, 6.92. Found: C, 70.87; H, 6.47; N, 6.92.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])=[O:10])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:8]([CH:9]([OH:10])[C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])=[C:7]([CH:20]([CH3:21])[CH3:22])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2]
Reactant: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCn1c(C(O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (3) (0.700 g, 2.15 mmol) in ethanol (61 mL) at 0° C. was added sodium borohydride (0.081 g, 2.15 mmol) and the reaction mixture was stirred at 0° C. for 2 h, then at room temperature overnight. More sodium borohydride (0.081 g, 2.15 mmol). was then added, and the mixture was stirred for 24 h. More sodium borohydride (0.081 g, 2.15 mmol) was again added, and stirring was continued for 6 h. The reaction mixture was concentrated and quenched with saturated NH4Cl solution, acidified with 1N HCl and then extracted with ethyl acetate (2×). The combined organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 30 to 60% ethyl acetate/hexane) to give impure product. The impure product was purified again by flash column chromatography (silica gel, 0 to 5% methanol/dichloromethane), followed by purified by flash column chromatography (silica gel, 40 to 60% ethyl acetate/hexane) to give a white solid (0.31 g, 44%). 1H NMR (300 MHz, CD3OD): 7.55 (s, 1H), 7.47 (s, 1H), 7.43 (s, 1 H), 6.18 (s, 1H), 3.73 (q, J=6.9 Hz, 2H), 3.12-3.07 (m, 1H), 2.37 (s, 3H), 1.30 (d, J=7.2 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 0.92-0.84 (m, 3H); Mass Spectrum: 328.1 (M+H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[C:9]([O:16][CH3:17])=[CH:10][C:11]([F:15])=[C:12]([CH:14]=1)[NH2:13].N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[C:9]([O:16][CH3:17])=[CH:10][C:11]([F:15])=[C:12]([NH:13][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1cc(F)c(N)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(Br)c(OC)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 73.5 %

Procedure:
At 0° C., ethansulfonylchloride (1.4 g, 10.9 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-4-methoxyaniline (3.5 g, 24.0 mmol) in pyridine (1.3 g, 16.4 mmol) and dry CH2Cl2 (20 mL). After stirring at room temperature for 10 h, CH2Cl2 extractive work up and purification by silica gel chromatography (PE:EA=10:0 to 3:1) gave the title compound (2.5 g, 73.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=8.4 Hz, 1H), 6.73 (d, J=11.6 Hz, 1H), 6.27 (s, 1H), 3.89 (s, 3H), 3.10 (q, J=7.6 Hz, 2H), 1.40 (t, J=7.6 Hz, 3H). LCMS: 334.0 (M+Na)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=O.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH2:25])[CH3:24])=[CH:22][C:17]=2[O:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH:25][C:8](=[O:10])[CH:7]=[CH:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:24])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: CC(N)c1ccc2c(c1)OCO2
Reactant: COc1cccc(C=CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C=CC(=O)NC(C)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A mixture of 3-methoxycinnamic acid (2 mmole), (±)-1-benzo[1,3]dioxol-5-yl-ethylamine, Preparation 2 (396 mg, 2.4 mmole), EDC hydrochloride (768 mg, 4 mmole), DMAP (244 mg, 2 mmole), and triethylamine (404 mg, 4 mmole) in CH2Cl2 (5 mL) was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with CH2Cl2 (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was subjected to purification by flash column chromatography on silica gel eluted with EtOAc/hexane (2:1) to provide the racemic titled compound (510 mg, 78%).
Reaction SMILES: ClC(OC(C)C)=O.C[N:9]1CCOCC1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].N.C(N(CC)CC)C>CN(C)C=O.CCOCC>[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([NH2:9])=[O:31])[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16]
Reactant: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Reactant: CN1CCOCC1
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl chloroformate (1M in toluene, 1.076 mL, 1.076 mmol) and then N-methyl morpholine (0.118 mL, 1.076 mmol) were added to a stirred mixture of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.233 g, 0.978 mmol) in dimethylformamide (4.7 mL) under nitrogen at −10° C. to −15° C. The reaction mixture was stirred for one hour at this temperature then ammonia (0.5 M solution in 1,4-dioxane, 3.91 mL, 1.956 mmol) and triethylamine (0.136 mL, 0.978 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was allowed to stir at −10° C. to −15° C. for one further hour then allowed to warm to room temperature. After 64 hours, ether (10 mL) was added and the precipitate was washed with ether (10 mL), acetonitrile (10 mL) and water (4×10 mL) to afford the title compound. Yield 105 mg, 0.443 mmol, 45%. LCMS (ES+), m/z 238 (M+H)+ at the solvent front. 1H NMR (400 MHz, d6-DMSO) δ: 8.88 (1H, s), 7.84 (1H, br s), 7.72 (1H, br s), 7.70 (1H, br s), 7.44 (1H, br s) 4.88 (2H, s).