Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][O:5][CH:4]([C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH2:3][CH2:2]2.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>CO.O>[N:20]([C@@H:1]1[CH2:2][CH2:3][C@@H:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:5][CH2:6][C@H:7]1[OH:8])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC2OC2CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CO1
Temperature: 70 °C

Procedure:
To a solution of 5-(5,8-dioxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-pyrazole (2.7 g, 11.3 mmol, intermediate 19) in MeOH/water (60 mL/15 mL) was added ammonium chloride (1.51 g, 28.3 mmol) and sodium azide (3.67 g, 56.5 mmol). The mixture was heated at 70° C. behind a blast shield for 4 hr. The MeOH was removed under reduced pressure and the aqueous residue extracted with EtOAc (100 mL). The organic layer was washed with aqueous NaHCO3 (3×20 mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) followed by chiral SFC chromatography gave (3S,4R,7S)-4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol as the second eluting isomer as a clear gum (1.4 g, 41%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.43-5.37 (m, 1H), 4.18 (dd, J=13.9, 2.1 Hz, 1H), 4.06 (s, 3H), 3.97-3.77 (m, 3H), 2.45 (d, J=3.9 Hz, 1H), 2.32-2.09 (m, 2H), 2.10-1.85 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H]1[C@H](C(O)=O)CC=CC1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC=CC[C@H]1C(=O)O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 155.6 %

Procedure:
A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72 g) was dissolved in CH2Cl2 (750 mL) prior to the addition of CDI (50.9 g). After 2.5 h water was added, and the solution was extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated. The resulting material was dissolved in CH2Cl2 and ammonia gas was bubbled through the solution for 1.5 h. After stirring overnight, the majority of the solvent was removed and Et2O was added. The product precipitated as a white solid and was collected to give (1R,6S)-6-carbamoyl-cyclohex-3-enyl)-carbamic acid benzyl ester (61.5 g). MS found: (M+H)+=275.3.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:19])([CH3:18])[CH3:17]>>[CH:16]([NH:19][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14])([CH3:18])[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CC(C)N
Product: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1C
Yield: 79.9 %

Procedure:
4-Chloro-3,5-dinitro-o-xylene (10.0 grams, 0.043 mole) and isopropylamine (10.1 grams, 0.17 mole) are mixed and refluxed for 12 hours using an efficient reflux condenser. The mixture is then cooled and poured into 100 ml. of 5% hydrochloric acid and extracted with diethyl ether. The ether extract is dried over magnesium sulfate. Removal of the drying agent and solvent leaves an orange oil which readily solidifies. The product is recrystallized from methanol to give 8.7 grams (80%) of an orange solid with melting point 69° C. to 70° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:17](=O)[O:16]C(C)(C)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([OH:14])[C:18]=1[CH:17]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2c(OCc3ccccc3)cccc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1c(O)cccc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A solution of 5-(benzyloxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (Example 38A, 4.00 g, 14.07 mmol) in dichloromethane (80 mL) was cooled to −78° C. and treated with a solution of diisobutylaluminum hydride (6.00 g, 42.2 mmol) in toluene (40 mL) added dropwise over 20 min. The resulting mixture was then stirred at −78° C. for 3 h. The reaction mixture was quenched by the careful addition of methanol (5 mL) added dropwise over 15 min, followed by 4 N hydrochloric acid (20 mL) added dropwise over 15 min. The cooling bath was then removed and an additional 80 mL of 4N hydrochloric acid was added over 10 min and the mixture was stirred vigorously at 22° C. for 4 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting oil was chromatographed on silica gel (4×10 cm, elution toluene) to give 2.25 g (70% yield) of the title material as a pale yellow solid. LC (Method A): 2.219 min. HRMS (ESI) calcd for C14H13O3 [M+H]+ m/z 229.0859, found 229.0859. 1H NMR (CDCl3, 600 MHz) δ ppm: 5.12 (s, 2H), 6.43 (d, J=8.25 Hz, 1H), 6.52 (d, J=8.46 Hz, 1H), 7.34-7.4 (m, 6H), 10.39 (s, 1H), 11.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:36]>O1CCCC1>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:8][N:5]4[C:6]([Cl:36])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (100 mg, 0.25 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. was added n-butyllithium (0.5 mL of 1.6 M solution in hexanes, 0.8 mmol). The resulting reaction mixture was stirred at −78° C. for 10 minutes, followed by addition of carbon tetrachloride (1 mL) and stirring at −78° C. for additional 20 minutes. The reaction was then quenched by the addition of water. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vocuo. The resulting residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give 50 mg (45%) of N-cyclopentyl-4-[5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine as a yellow foam. 1H NMR (CDCl3): δ 8.53 (broad s, 1H), 8.06 (d, 1H), 7.63 (m, 2H), 7.15 (t, 2H), 7.05 (d, 1H), 6.27 (d, 1H), 5.17 (d, 1H), 4.35 (m, 1H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); 19F NMR (CDCl3): δ 112.2; MS m/z 442 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCOC(=O)c1ccc(C)c(N)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(NC(=O)C2=C(C)OCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Thionyl chloride (4.5 g, 0.038 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0,037 mole) and methylene chloride (100 ml). The mixture was warmed to 30°-35° C. for 3 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of ethyl 3-amino-4-methylbenzoate (6.7 g, 0,037 mole) and tziethylamine (4.0 g, 0,040 mole) in methylene chloride (100 ml). The reaction mixture was stirred overnight at room temperature and then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent gave an oil, which solidified. After recrystallization from ethanol (30 ml), the product (7.1 g, 59% yield) melted at 105°-107° C.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:16]([O:18][C:19](=[O:35])[CH:20]([C:25]1[S:29][N:28]=[C:27]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[N:26]=1)[CH2:21][C:22]([OH:24])=O)[CH3:17].C(Cl)Cl.[O:39]1[C:43]2[CH:44]=[CH:45][C:46]([CH2:48][CH2:49][NH2:50])=[CH:47][C:42]=2[O:41][CH2:40]1>CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:35])[CH:20]([C:25]1[S:29][N:28]=[C:27]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[N:26]=1)[CH2:21][C:22]([NH:50][CH2:49][CH2:48][C:46]1[CH:45]=[CH:44][C:43]2[O:39][CH2:40][O:41][C:42]=2[CH:47]=1)=[O:24])[CH3:17]
Reactant: CCOC(=O)C(CC(=O)O)c1nc(-n2ccnc2)ns1
Reactant: NCCc1ccc2c(c1)OCO2
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)NCCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.5 %

Procedure:
BOP-Cl (784 mg, 3.08 mmol) was added all at once to a solution 2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-succinic acid 1-ethyl ester (389 mg, 1.54 mmol) and DCM (10 mL) and stirred at room temperature for 30 min prior to addition of 2-benzo[1,3]dioxol-5-yl-ethylamine (620 mg, 3.08 mmol) and TEA (859 μL, 6.16 mmol). The reaction mixture stirred at r.t. for an additional 20 h. The solvent was evaporated to afford a white slurry oil, diluted with EtOAc (50 mL), washed with sat. NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 17 mg (3%) of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-succinamic acid ethyl ester as a white solid. [M+H]+ 443.90; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.74 (s, 1H), 7.15 (s, 1H), 6.66-6.52 (m, 3H), 6.04 (br s, 1H), 5.86 (s, 2H), 4.31 (q, 2H), 3.78 (t, 1H), 3.63 (t, 2H), 3.16 (t, 2H), 2.83 (d, 2H), 1.32 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.OS(O)(=O)=O.[CH3:20]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:20])=[O:13])[CH:6]=[CH:5]2
Reactant: CO
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(O)ccc2c1
Yield: 95 %

Procedure:
To a 1-L round bottomed flash equipped with a nitrogen inlet and magnetic stir bar was added 50 g (0.27 mol) of 6-hydroxy-2-naphthoic acid and 400 mL of methanol. The suspension was treated slowly with 1 mL of con. H2SO4 and stirred at room temperature overnight. The resulting solution was evaporated, taken up in 500 mL of ethyl acetate and washed sequentially with 3×300 mL of saturated NaHCO3, 2×300 mL of water and brine. The pale yellow solution was dried over MgSO4, reduced in volume to about 100 mL and slowly treated with hexane. The resulting crystalline precipitate was collected and dried under a stream of nitrogen to yield 52 g (95%) of the title compound as fine, white plates, mp 196° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[S:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1.C(Cl)CCl>CN(C=O)C>[S:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1
Reactant: Nc1ccc(C(=O)N2CCSC2)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCSC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (46 mg, 0.14 mmol) and 4-(thiazolidin-3-ylcarbonyl)phenylamine (30 mg, 0.14 mmol) in DMF (2 mL), EDC (54 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (15 mg). MS 509.2 and 511.2 (M+H, Cl pattern).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[CH3:18])[CH2:13][CH3:14]
Reactant: CCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 2-methyl-benzoyl chloride (5.95 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 9.61 g of yellow liquid. MS: m/e 319(M+′+1), 318(M+′), 273, 259, 199, 183, 153, 119(base), 91, 77.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][CH3:24]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([N:23]([CH3:24])[CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CNCCN(C)C
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Product: CN(C)CCN(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
0.118 g (0.0003 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 5 ml of dioxane and treated with 0.39 ml of N,N,N'-trimethylethylenediamine. The mixture was stirred at room temperature for 20 hrs., the solvent was removed and the residue was chromatographed on silica gel with 5% methanol in dichloromethane. There was obtained 0.123 g (99%) of N-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-N,N',N'-trimethylethane-1,2-diamine as a light yellow, amorphous solid. MS (ISP): me/e=415, 413 (C16H21BrN4O2S+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:23]([Mg]Br)#[CH:24].O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:23]#[CH:24])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Reactant: C#C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a cold (−78° C.) suspension of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was added ethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol). The reaction mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was poured into water and adjusted to neutral pH with 1N aqueous hydrochloric acid. The aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration provided 1-[2-(4-fluorophenyl) -6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (11.9 g, 96%) as a tan solid. Rf 0.18 (4:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35 (d, 1H), 7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MS m/z 335 (M+1).
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[CH:4]1[C:15]([O:17]CC)=O.C(=O)([O-])O.[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[N+:12]([C:8]1[CH:7]=[C:6]([CH:5]2[CH:4]3[CH:3]2[CH2:2][N:34]([CH2:33][CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]3=[O:17])[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C1C(CBr)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2C(CN1CCCc1ccccc1)C2c1cccc([N+](=O)[O-])c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 2-(bromomethyl)-3-(3-nitrophenyl)cyclopropane carboxylate (Preparation 23, 60 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (30 mg, 0.36 mmol) and 3-phenylpropylamine (30 mg, 31 μl, 0.22 mmol). The mixture was heated to 150° C. for 1 hour, then cooled to room temperature and stirred for 16 hours. Water (30 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). The combined extracts were concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with dichloromethane then 4:1 dichloromethane:ethyl acetate. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glassy solid (55 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-])=O>CO.C1COCC1.[Ni]>[NH2:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(C)s1
Temperature: 25 °C
Reaction time: 36 h
Yield: 64.3 %

Procedure:
To a solution of methyl 5-methyl-4-nitrothiophene-2-carboxylate (F-3) (14.8 g, 73.6 mmol) in MeOH/THF (1:1, 300 mL) was added Raney Ni. The reaction mixture was degassed and charged with hydrogen 3 times, and then stirred at room temperature for 36 h under 1 atmosphere of hydrogen. Raney Ni was filtered, and the filtrate was concentrated. The residue was treated with aqueous HCl (1 N, 150 mL) and filtered. The filtrate was treated with aqueous NaOH (1 N) to bring pH to about 8 to 9. Then the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, and the solvent was removed to give the title compound (8.1 g).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=C[CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC(N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][CH:45]5[CH2:44][N:49]([CH3:48])[CH2:46]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CN(C)C4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine bis-hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.10 (m, 8 H) 2.32 (br. s., 3 H) 3.08 (t, J=6.82 Hz, 2 H) 3.29 (br. s., 3 H) 3.62 (t, J=6.95 Hz, 2 H) 3.82 (m, 2 H) 3.94 (br. s., 3 H) 4.44 (m, 1 H) 4.88 (m, 1 H) 5.38 (d, J=12.13 Hz, 2 H) 5.99 (m, 1 H) 7.50 (br. s., 2 H) 7.84 (br. s., 1 H) 8.13 (br. s., 1 H)) 8.31 (d, J=8.0 Hz, 1 H) 8.65 (d, J=7.83 Hz, 1 H). [M+H] calculated for C27H34FN7O3, 524; found 524.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[N:10][C:9]3=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp >205° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.70 (m, 9H), 3.70-4.00 (m, 7H), 4.95 (brs, 1 H), 6.64-6.94 (m, 3 H), 7.01(d, J=8.9 Hz, 2 H), 7.27-7.30(m, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 262.0 ((M+2H)2+, 100%); 523.0 (MH+, 10%); HRMS Calcd. for C27H35N6O3S (MH+): 523.2491. Found: 523.2511.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:37]([Cl:38])=[CH:36][CH:35]=[C:34]([Cl:39])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:34]([Cl:39])=[CH:35][CH:36]=[C:37]([Cl:38])[C:30]=3[Cl:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4c(Cl)ccc(Cl)c4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3,6-trichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 571.