Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[C:5]([F:27])=[CH:4][N:3]=1.[CH3:28][O-:29].[K+]>CN1C(=O)CCC1>[F:27][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[N:7][C:2]([O:29][CH3:28])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3nc(Cl)ncc3F)CC2)CC1
Reactant: C[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(F)c(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The tert-butyl 1′-(2-chloro-5-fluoropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (40 mg, 0.10 mmol) was added to NMP (1 mL), and then potassium methoxide (8.1 mg, 0.11 mmol) was added to the mixture. The reaction was stirred for 30 min at r.t. and was quenched with ammonium chloride solution (5 mL), extracted with ethylacetate (10 mL). The organic phase was washed with brine (10 mL, ×1), dried over magnesium sulfate, filtered and concentrated by rotavapor. The crude mixture was purified by preparative TLC with 30% acetone: hexane to yield the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[Br:15][C:16]1[CH:17]=[C:18]2[C:29](=[CH:30][CH:31]=1)[O:28][C:21]1[C:22]([F:27])=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[N:32]S(C(C)(C)C)=O>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]3([C:11]4[C:8](=[CH:7][CH:14]=[CH:13][CH:12]=4)[C:9]([NH2:10])=[N:32]3)[C:20]3[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([F:27])[C:21]=3[O:28][C:29]2=[CH:30][CH:31]=1
Reactant: N#Cc1ccccc1Br
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2ccccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 0.75 mL, 1.2 mmol, Aldrich) was added dropwise to a solution of 2-bromobenzonitrile (219 mg, 1.2 mmol, Oakwood Products) in THF (30 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was allowed to stir for 5 min at −78° C. Subsequently, a solution of N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (400 mg, 0.93 mmol, step 1) in THF (30 mL) was added. After 5 min, the reaction mixture was quenched with aqueous, saturated solution of NH4Cl and EtOAc was added. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (55-100% EtOAc/hexanes) to afford the title compound as a yellow solid. MS m/z=431.9 [M+H]+. Calculated for C19H10BrClFN3O: 430.7.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][NH:9][CH3:10].[C:11]([O:15][C:16]([NH:18][S:19](N1C=CC(=[N+](C)C)C=C1)(=[O:21])=[O:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][O:5][CH2:4][C@H:3]1[CH2:8][N:9]([CH3:10])[S:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])(=[O:20])=[O:21]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CNCC1COCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C[C@@H]1COCCO1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (0.760 g, 4.55 mmol), N-[1-{[(tert-butoxycarbonyl)amino]sulfonyl}pyridin-4(1H)-ylidene]-N-methylmethanaminium (1.51 g, 5.00 mmol), and triethylamine (1.55 mL, 11.4 mmol) were slurried in 50 mL dichloromethane and stirred at ambient temperature. After 12 hours, the solution was concentrated in vacuo and purified by silica chromatography (50-100% ethyl acetate/hexanes gradient) to afford the title compound. LRMS (APCI) calc'd for (C11H22N2O6SNa) [M+Na]+, 333.1; found, 333.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:28]3[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)n3)cc(C)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
A solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.30 g, 13.20 mmol) in DMF (10 mL) was treated with cesium carbonate (13.30 g, 40.82 mmol) at 0° C. followed by 2,4-dichloropyrimidine (3.90 g, 26.20 mmol). The mixture was stirred at room temperature for 24 hours. The suspension was quenched with ice water, acidified with 2N HCl and extracted with ethyl acetate. The extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane; 1:1 then MeOH/CH2Cl2; 1:99 gradient) to give [6-(2-chloro-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester as a yellow foam (3.00 g, 63%). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=5.85 Hz, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 6.98 (d, J=5.85 Hz, 1H), 5.65 (dd, J=8.20, 2.73 Hz, 1H), 4.14-4.07 (m, 2H), 3.18 (dd, J=15.22, 2.73 Hz, 1H), 2.52 (dd, J=15.22, 8.20 Hz, 1H), 2.39 (s, 3H), 1.19 (t, J=7.03 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]=[O:26])([CH3:19])([CH3:18])[CH3:17].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([O:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:24]([CH:27]=1)[CH:25]=[O:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C(C)(C)C)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-tert-butyl-2-hydroxybenzaldehyde (356 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(Cl)Cl.[CH3:10][N:11]1C(C(O)=O)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1>CN(C)C=O>[CH3:10][N:11]1[C:1]([C:2]([Cl:4])=[O:3])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(-c2cnn(C)c2C(=O)O)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(-c2cnn(C)c2C(=O)Cl)n1
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.85 ml) was added to a mixed solution of methylene chloride (5 ml) and N,N-dimethylformamide (5 μl) containing the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid (210 mg) obtained in (Example 3.3) <Step 1>, and the obtained mixture was then stirred for 2 hours. Thereafter, the reaction solution was concentrated under reduced pressure to obtain a crude product (230 mg) of the title compound in the form of an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=NO)[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2].Cl.[OH2:18]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:18])[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2]
Reactant: O=C1C=CC(=NO)c2c1cccc2[N+](=O)[O-]
Reactant: O
Agent: [Fe+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 33 °C
Reaction time: 1.5 h

Procedure:
5.5 g of 8-nitro-1,4-naphthoquinone-1-oxime are suspended in 450 ml of 38 percent by weight aqueous hydrochloric acid, followed by heating to 33°C. 61 g (0.22 mol) of iron (II) sulphate heptahydrate are then introduced in portions with stirring. After 1.5 hours, the reaction mixture is poured into 1000 ml of water heated to approximately 50°C, followed by stirring for 1 hour at that temperature. The reaction product precipitated is filtered off under suction, washed with water until neutral and dried at approximately 50°C. The yield amounts to 4 g (78 percent of the theoretical yield) of 5-nitro-1,4-naphthoquinone melting at 160°C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1.[CH3:11]OS(OC)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:11][O:9][C:8]1[C:3]([CH2:2][OH:1])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(O)c(CO)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccc(C)nc1CO
Yield: 84.9 %

Procedure:
To a solution of 2-(hydroxymethyl)-6-methylpyridin-3-ol (1.23 g, 8.84 mmol) in acetone (25 mL) was added Me2SO4 (1 mL, 10.6 mmol), followed by Cs2CO3 (3.6 g, 11.05 mmol). The reaction was refluxed for 2 h. The reaction was filtered and concentrated to give a red oil which was purified by column chromatography on ISCO (40 g) with 0-80% ethyl acetate in hexanes over 25 minutes to yield (3-methoxy-6-methylpyridin-2-yl)methanol(1.15 g, 85% yield) as a off-white solid. HPLC retention time (Method B)=0.17 min. 1H NMR (CDCl3, 400 MHz) δ ppm 2.49 (s, 3H), 3.83 (s, 3H), 4.45 (s, 1H), 4.70 (s, 2H), 7.03 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39]CC)=[O:38])=[CH:32][C:31]=3[Cl:42])[CH:19]=2)=[C:8]([Cl:43])[CH:7]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28]/[CH:27]=[CH:26]/[C:25]#[C:24][C:20]2[CH:19]=[C:18]([C:17]#[C:16]/[CH:15]=[CH:14]/[CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:44])=[O:3])=[CH:7][C:8]=3[Cl:43])[CH:23]=[CH:22][CH:21]=2)=[C:31]([Cl:42])[CH:32]=1)([OH:39])=[O:38]
Reactant: CCOC(=O)Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(CC(=O)OCC)cc3Cl)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(CC(=O)O)cc3Cl)c2)c(Cl)c1

Procedure:
To a solution of (E)(E) [3-chloro-4-(5-{3-[5-(2-chloro-4-ethoxycarbonylmethyl-phenoxy)-pent-3-en-1-ynyl]-phenyl}-pent-2-en-4-ynyloxy)-phenyl]-acetic acid ethyl ester (example 7) (180 mg 0.28 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (1.5 mL).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](O)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:26]([C:22]2[N:23]=[CH:24][O:25][C:21]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:27])=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(F)(F)CCCCn1ccc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:64])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:34][C:33]=2[C:44]2[CH:49]=[C:48]([C:50](=[O:63])[NH:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=3)[CH:47]=[CH:46][N:45]=2)[N:25]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC2C=CC([N+]([O-])=O)=CC=2)=[O:12])[CH2:7][CH2:6]1.[CH3:65][O:66][CH2:67][CH2:68][NH2:69].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:65][O:66][CH2:67][CH2:68][NH:69][C:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:64])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]4)=[CH:34][C:33]=3[C:44]3[CH:49]=[C:48]([C:50](=[O:63])[NH:51][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:60])([F:62])[F:61])[CH:54]=4)[CH:47]=[CH:46][N:45]=3)[N:25]=2)[CH2:10][CH2:9]1)=[O:12]
Reactant: CN(CCN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Reactant: COCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-nitrophenyl 4-(2-(methyl((6-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)pyridin-2-yl)methyl)-amino)ethyl)piperazine-1-carboxylate (100 mg, 0.11 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 2-methoxyethanamine (10 mg, 0.13 mmol, 1.00 equiv), and N,N-diisopropylethylamine (45 mg, 0.35 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The mixture was concentrated under vacuum. The crude product (0.1 g) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 23.2 mg (18%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.76 (s, 1H), 9.54-9.52 (m, 1H), 9.05-9.03 (m, 1H), 8.48-8.45 (m, 1H), 8.26 (m, 1H), 8.14-8.12 (m, 2H), 7.88-7.86 (m, 1H), 7.79-7.24 (m, 7H), 6.71 (m, 1H), 4.65-4.63 (d, J=5.7 Hz, 2H), 4.09 (m, 3H), 3.69-3.01 (m, 23H), 1.71-1.59 (m, 6H). MS (ES, m/z): 816 [M+H]+.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1(C)C=CC=CC=1>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: CCOC(=O)CCCBr
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCC(=O)OCC
Yield: 58.2 %

Procedure:
A solution of dioctadecylamine (5.2 g., 0.01 mole), ethyl 4-bromobutyrate (1.95 g., 0.01 mole) and toluene (50 ml.) is heated at reflux for sixteen hours, then cooled and concentrated in vacuo to a semi-solid oil. The oil is triturated with ethylacetate, filtered, and the filtrate washed with water, then dried (Na2SO4). Removal of the solvent gives the product as an oil (3.7 g.).
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.C([Li])CCC.[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=O)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.CCCCCC>[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=[CH:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.8 g (22.6 mmol) 3-pyridylmethyltriphenylphosphonium chloride in 40 ml dry tetrahydrofuran at 0° is added slowly 9.0 ml (22.5 mmol) of 2.5M n-butyllithium in hexane. After stirring the resulting deep red solution at room temperature for 0.5 h, a solution of 3.23 g (9 mmol) of methyl 2,2-dimethyl-4-formylmethyl-8-(t-butyldimethylsilyloxy)-octanoate in 10 ml dry tetrahydrofuran is added slowly and then stirred for 16 h. The reaction is quenched by addition of saturated ammonium chloride solution and then extracted thrice with ether. The combined organic extracts are washed with water and brine, dried, filtered and concentrated. The residue is taken up in ether and the resulting precipitate is removed by filtration. The filtrate is evaporated and the residue is purified by silica gel chromatography using 1:1 hexane/ether to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsilyloxy)-octanoate; NMR (CDCl3): delta 5.7-6.4 (m,2H), 3.63 and 3.60 (two s,3H), 1.2 and 1.15 (two s,6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([I:14])[CH:5]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([I:14])[C:7]([NH2:13])=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(I)c(N)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(N)c(I)c1
Temperature: 70 °C

Procedure:
To a solution of 4-amino-3-iodo-5-nitro-benzoic acid methyl ester in ethyl acetate (50 mL) was added SnCl2 dihydrate. The mixture was heated to 70° C. for two hours, then cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide 1.68 g (quantitative) of 3,4-diamino-5-iodo-benzoic acid methyl ester.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9][CH:8]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]2.C(Cl)Cl.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>[Cl-]>[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:1][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])[CH2:6]2
Reactant: C1=C2CCCCNN2CCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Yield: 54.3 %

Procedure:
Into a solution of 4.0 g of this product in pyridinemethylene chloride is added 8.39 g of diazabicyclo[5.4.0]undeca-7-ene. Subsequently, under cooling, a methylene chloride solution of 3.36 g of benzenesulfonyl chloride is added dropwise with stirring. After the reaction, water is added, and the organic layer is separated, followed by evaporation of the solvent. The residue is crystallized from an ethanol-n-hexane mixture, purified through silica gel column chromatography, and recrystallized from an ethyl acetate-n-hexane mixture to give 2.98 g of 5-amino-2-benzenesulfonylaminoindan.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([CH3:26])[CH3:25])[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:2]2[CH:7]=[C:6]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([CH3:25])[CH3:26])[N:18]=4)=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]4[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)Nc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Reactant: NC1CCCC1
Product: CC(C)Nc1nccc(-c2c(-c3ccnc(NC4CCCC4)c3)nn3ccccc23)n1
Yield: 64 %

Procedure:
A solution of crude 4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine (204 mg, 0.586 mmol) in cyclopentylamine (2 mL, 20.3 mmol) was heated at 135° C. in a sealed glass tube for 16 hours. The reaction mixture was cooled and the excess cyclopentylamine was removed in vacuo. The resultant residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (1:1 hexanes:ethyl acetate to 100% ethyl acetate) provided N-cyclopentyl-N-(4-{3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}-2-pyridinyl)amine (155 mg, 640%). Rf 0.16 (1:2 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.49 (d, 1H), 8.39 (d, 1H), 8.13–8.08 (m, 2H), 7.29 (t, 1H), 6.89 (t, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 6.46 (d, 1H), 5.23 (br, 1H), 4.86 (d, 1H), 4.21 (m, 1H), 3.93 (m, 1H), 1.95 (m, 2H), 1.70–1.42 (m, 6H), 1.27 (d, 6H); MS m/z 414 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]1[N:14]2[C:15]3[CH:7]([CH2:8][CH2:9][C:10](=[O:16])[C:11]=3[CH:12]=[CH:13]2)[CH2:6][NH:5][CH2:4]1.I[CH3:18]>CN(C)C=O>[CH3:18][CH:9]1[CH2:8][CH:7]2[CH2:6][NH:5][CH2:4][CH2:3][N:14]3[C:15]2=[C:11]([CH:12]=[CH:13]3)[C:10]1=[O:16]
Reactant: O=C1CCC2CNCCn3ccc1c32
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC2CNCCn3ccc(c32)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 731.3 %

Procedure:
Add sodium hydride (0.78 g, 1.9 mmol, 60% in mineral oil) to 1,2,4,5-tetrahydro-6H-[1,4]diazepino[6,7,1-hi]indol-7-one (3.05 g, 1.62 mmol) in dry dimethylformamide (77 mL). Stir for 30 minutes at room temperature and then add iodomethane (2.0 mL, 3.2 mmol). Stir at room temperature for 134 minutes. Partition between ethyl acetate (1 L) and water (500 mL). Wash the organic phase with saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to chromatography (pre-packed silica gel), eluting with a gradient 1:0-9:1 ethyl acetate/methanol to provide the desired compound (2.42 g, 74%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:11]C(=O)OCC)[S:8][C:6]=2[N:7]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH2:11])[S:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)Nc1nc2cnc(Cl)nc2s1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc2nc(N)sc2n1
Temperature: 25 °C
Yield: 82 %

Procedure:
Ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (250 mg, 0.966 mmol) was suspended in MeOH (10 mL) and a 25% (w/w) solution of sodium methoxide in methanol was added (10 mL, 46.3 mmol). The resulting solution was refluxed overnight, cooled to ambient temperature, poured into an equal volume of water and extracted with chloroform (4×). A significant amount of compound was still present in the aqueous phase, so this was concentrated to residue, and then dissolved in a small amount of 1N HCl (not enough to make the resulting solution acidic) and extracted again with EtOAc (5×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. 5-Methoxythiazolo[5,4-d]pyrimidin-2-amine (144 mg, 0.790 mmol, 82% yield) was thus obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1H) 7.81 (s, 2H) 3.90 (s, 3H). MS (LC/MS) R.T.=0.73; [M+H]+=183.03.