Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([S:15]([OH:18])(=O)=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:21]>>[CH2:1]([S:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([S:15]([Cl:21])(=[O:18])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCSc1nc2ccc(S(=O)(=O)O)cc2s1
Product: CCCCSc1nc2ccc(S(=O)(=O)Cl)cc2s1
Reaction time: 1 h

Procedure:
2-mercaptobenzthiazol (83.4 g, 0.5 mol) was dispersed in 100 mL of methanol, and added a solution containing 24 g of NaOH in 50 mL of H2O. When 2-mercaptobenzthiazol was completely dissolved, n-butylbromide (54 mL, 0.5 mol) was added and the reaction solution was refluxed for 12 hours. Then, methanol was removed from the solution under reduced pressure and 300 mL of ethylacetate was added to the solution which was then washed with H2O and 1M K2CO3 in a sequential order. The separated organic solution was dried over MgSO4 and then distilled under reduced pressure to give about 100 g of pure 2-n-butylthio-6-benzthiazol (89%), which was subsequentially transferred to a flask of 500 mL without further purification and cooled down to a temperature of 0° C. Chlorosulfonic acid (130 g, 2.5 equi.) was slowly added into the flask. The reaction solution was reacted for 24 hours at about 110° C. When starting material was completely exhausted, the reaction solution was cooled down to room temperature (RT) and stirred vigorously after adding ice water. Then, the solid product was obtained by filtering. The filtered solid was treated with ethylacetate (300 mL) followed by stirring for 1 hour. The undissolved solid was filtered and washed with ethylacetate to give 2-n-butylthio-6-benzthiazolsulfonic acid (30 g). The filtrated ethylacetate solution was treated with 5 g of activated carbon and MgSO4 and stirred for 1 hour. Then, the ethylacetate solution was filtered on activated carbon and MgSO4 again and dried under reduced pressure to remove the solvent, to give the titled compound, 2-n-butylthio-6-benzthiazolsulfonyl chloride (about 60 g) in a solid form. The titled compound was treated with n-hexane (150 mL), followed by stirring for 1 hour. After filtering, pure 2-n-butylthio-6-benzthiazolsulfonyl chloride (55 g) was obtained. A 30 mL of SOCl2 as solvent and as reagent was added to 2-n-butylthio-6-benzthiazolsulfonic acid (30 g) obtained above. The reaction solution was refluxed for 5 hours, dried under reduced pressure, and then, treated with H2O. The solid product was obtained by filtering. The solid was stirred with ethylacetate (100 mL) for 1 hour. The ethylacetate solution was treated with 5 g of activated carbon and MgSO4 and stirred for 1 hour. The solution after filtering on activated carbon and MgSO4 was dried under reduced pressure to remove the solvent, to give the titled compound, 2-n-butylthio-6-benzthiazolsulfonyl chloride (about 30 g) in a solid form. The compound was purified with n-hexane as described above, to give a pure 2-n-butylthio-6-benzthiazolsulfonyl chloride (25 g). Consquently, about 80 g of titled compound (about 56%) was prepared by two processes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]3[CH:19]=2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]3[C:19]=2[C:20](=[O:22])[CH3:21])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccn2cc(-c3ccc(F)cc3)nc12
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(-c2ccc(F)cc2)nc2c([N+](=O)[O-])cccn12
Yield: 55 %

Procedure:
2-(4-Fluorophenyl)-8-nitroimidazo[1,2-α]pyridine (2 g, 7.8 mmol) was added to acetic anhydride (15 mL). To this mixture was added a catalytic amount of concentrated sulfuric acid and the reaction mixture was heated to reflux for 1 hour. The resulting mixture was concentrated to a slurry, neutralized by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give 1.3 g (55%) of 1-[2-(4-fluorophenyl)-8-nitroimidazo[1,2-α]pyridin-3-yl]ethanone as a brown solid. 1H NMR (DMSO-d6): δ 9.93 (d, 1H), 8.62 (d, 1H), 7.78 (q, 2H), 7.46 (m, 3H), 2.20 (s, 3H); MS m/z 300 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1N
Reactant: Clc1ncccc1-c1ccncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1Nc1ncccc1-c1ccncn1

Procedure:
4-(2-Chloro-pyridin-3-yl)-pyrimidine (60 mg, 0.30 mmol), N-(3-amino-4-methyl-phenyl)-3,4-dichloro-benzamide (107 mg, 0.36 mmol), Pd(OAc)2 (4 mg, 0.012 mmol), rac-BINAP (8 mg, 0.012 mmol) and K2CO3 (829 mg, 6.0 mmol) in toluene (3.0 mL) were reacted overnight at 130° C. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filter, concentrated and purified by reverse-phase HPLC (Gilson, acidic mobile phase) yielding the title compound. MS m/z=450, 452 [M]+ and [M+2]+. Calc'd for C23H17Cl2N5O: 450.33.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)=[C:16]([F:27])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:26][C:23]1[CH:22]=[N:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][C:16]=2[F:27])=[N:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cnc(-c2ccc(C3=CCNCC3)cc2F)nc1

Procedure:
4-[3-Fluoro-4-(5-fluoro-pyrimidin-2-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (21AB) (717 mg, 1.92 mmol, 1 equiv) was treated with 10% solution of trifluoroacetic acid in dichloromethane at room temperature overnight.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])=[CH:15][CH:14]=1.C(#N)C.CC(=CC)C.Cl([O-])=[O:35].[Na+]>O.C(OCC)(=O)C.C(O)(C)(C)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:35])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])=[CH:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(-c4ccccc4O)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 0 °C
Yield: 4 %

Procedure:
A round bottomed flask was charged with 6-fluoro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carbaldehyde (20 mg, 0.60 mmol), acetonitrile, (1.0 mL), t-butanol (1.0 mL) and cooled to 0° C. 2-methyl-2-butene (0.49 mL, 4.6 mmol) was then added. In a separate flask, sodium chlorite (102 mg, 1.20 mmol) and NaH2PO4 (170 mg, 1.23 mmol) were dissolved in water (1 mL) then added to the reaction. The reaction was sealed and reacted at room temperature for 15 h. Ethyl acetate and water were added and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC was then used to provide the title compound (8.4 mg, 40%). MS (ES−) 346.1 (M−H)−. Retention time: 1.86 min Waters Xbridge dC18 5 um 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.
Reaction SMILES: Cl[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[N:3][CH:4]=[C:5]([CH:9]=2)[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(F)cc2)c1
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5c, using 6-chloro-5-(4-fluoro-phenyl)-nicotinic acid and (hydroxymethyl)cyclopropane as starting materials, MS (ISP) 286.0 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1COCC1.C([Li])CCC.[I:28]I>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[I:28]
Reactant: II
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cc(F)c(I)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 3,5-difluoro-4′-propylbiphenyl (T-4) (18.0 g) and THF (200 ml) were added, and cooling was carried out to −74° C. Thereto, a n-butyllithium (1.57 M) n-hexane solution (56.4 ml) was added dropwise in a temperature range of −74° C. to −70° C., and stirring was carried out for another 1 hour. Subsequently, a THF (150 ml) solution of iodine (24.6 g) was added dropwise in a temperature range of −75° C. to −70° C., and stirring was carried out for 6 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (400 ml), and mixing was carried out. Toluene (300 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with an aqueous solution of sodium thiosulfate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by means of column chromatography (silica gel; heptane), and further purified by recrystallization from Solmix A-11, and thus 3,5-difluoro-4-iodo-4′-propylbiphenyl (T-5) (21.4 g) was obtained. The yield based on compound (T-4) was 77%.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[CH:28]=[CH:29][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.99 min, MH+ 393. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.13,(1H, s), 8.86,(1H, t), 8.34,(1H, d), 8.21,(1H, s), 8.07,(1H, d), 7.81,(1H, d), 7.57, (1H, d), 7.52,(1H, d), 7.29,(1H, d), 3.21,(2H, t), 2.45,(3H, s), 1.07,(1H, m), 0.47, (2H, m), 0.27,(2H, m).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15](=[O:17])[NH2:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O>CO.[Pd]>[C:15]([C@H:13]1[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:14]1)(=[O:17])[NH2:16]
Reactant: NC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H]1C[C@H](C(=O)O)N1
Yield: 96.2 %

Procedure:
53 mg (163 μmol) of cis-1-benzyl-4-carbamoyl-azetidine-2-carboxylic acid benzyl ester (II) in 10 ml of methanol are hydrogenated in a Parr shaker over 18 mg of 10% Pd/C under a hydrogen pressure of 3.3 atm for 3 hours. 10 ml of water is added, the mixture filtered through a fluted filter, and the catalyst washed with several portions of methanol. Evaporation and drying in vacuo (0.1 torr, 4 hours) affords 22.6 mg (96%) of a colorless glass. 1H NMR (D2O): δ5.00 (t, 1H, J=9), 4.75 (t, 1H, J=9), 3.14 (dt, 1H, J=10 (t), 12 (d)), 2.52 (dt, 1H, J=8(t), 12 (d)). IR (nujol): 3399, 3141, 3019, 2537, 2409, 1688, 1615, 1563, 1391, 1294, 1217, 1165, 1115, 1048, 968, 887, 810, 762, 696, 637 cm-1. Mass Spectra: EI: m/z 142(M-2H, 40%), 100 (100), 91 (14), 82 (27), 68 (28), 54 (50), 44 (95); CI (isobutane): m/z 145 (M+H, 100%), 126 (7), 100 (24), 99 (15), 84 (15), 72 (22).
Reaction SMILES: [CH2:1]([C:5]1[O:10][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:7]=2[N:6]=1)[C:2]([CH3:4])=O.[CH3:17][NH:18][NH2:19]>C(O)(=O)C>[CH3:17][N:18]1[C:5]([NH:6][C:7]2[C:8](=[CH:12][CH:13]=[C:14]([CH3:16])[CH:15]=2)[C:9]([OH:10])=[O:11])=[CH:1][C:2]([CH3:4])=[N:19]1
Reactant: CNN
Reactant: CC(=O)Cc1nc2cc(C)ccc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)O)c(Nc2cc(C)nn2C)c1
Yield: 49.3 %

Procedure:
The benzoxazinone of Example 1 (15.31 g., 0.071 mole) was added to a solution of methylhydrazine (3.90 g., 0.085 mole) in acetic acid (150 ml.) and the resultant solution was stirred at 80° C. for 2.5 hours. The solvent was removed and the product was recrystallized (acetonitrile) to yield N-(1,3-dimethyl-5-pyrazolyl)-4-methylanthranilic acid (8.59 g., 49 percent), mp 188°-192° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2[S:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[N:13]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:14]2[N:13]=[C:12]([C:10]3[S:9][C:8]4[C:3]([OH:2])=[CH:4][CH:5]=[CH:6][C:7]=4[CH:11]=3)[CH:17]=[CH:16][N:15]=2)[CH2:23][CH2:24]1
Reactant: COc1cccc2cc(-c3ccnc(NCCCN4CCN(C)CC4)n3)sc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCN(CCCNc2nccc(-c3cc4cccc(O)c4s3)n2)CC1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
[4-(7-Methoxy-benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methyl-piperazin-1-yl)-propyl]-amine (150 mg, 0.380 mmol) is dissolved in dry dichloromethane (10 mL) and the solution is cooled to −70° C. To the solution, boron bromide (BBr3) (1.0 M in dichloromethane, 2.64 mL) is added dropwise. The reaction is stirred at −70° C. for 15 minutes, then the cool bath is removed and the reaction is allowed to warm to ambient temperature overnight. After 16 hours, the reaction is again cooled to 70° C. Methanol (5 mL) is added to the reaction mixture then the mixture is allowed to warm to ambient temperature where it is concentrated in vacuo to an orange solid. The crude product is dissolved in THF (minimal) and purified by silica gel chromatography, eluting with MeOH/dichloromethane 0-40%, to yield the title compound as a solid (92.0 mg, 63% yield). ES+(m/z) 384 [M+H].
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@@H:13]([N:16]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@@H:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([O:26][C:35]5[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=5[F:29])=[O:25])=[CH:27][CH:28]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C#CCN(c1ccc(C(=O)O)cc1)[C@@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)[C@@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21
Yield: 68 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 3, p-[N-((6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with pentafluorophenol to give pentafluorophenyl p-[N-((6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoate in 68% yield.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[NH2:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][NH:7][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4]
Reactant: CC(C)(O)CCl
Reactant: NCCO
Product: CC(C)(O)CNCCO
Reaction time: 48 h

Procedure:
1-Chloro-2-methyl-2-propanol (135 ml) was added dropwise over 10 min to stirred 2-aminoethanol (400 ml) at 10° C. under nitrogen. The cooling bath was then removed and stirring was continued at room temperature for 48 h. A solution of sodium hydroxide (48.8 g) in methanol (440 ml) was added and the resulting white suspension was stirred for 10 min. The mixture was filtered through a pad of kieselguhr and the filtrate was concentrated under reduced pressure. The residual oil was distilled in vacuo to give 1-[(2-hydroxyethyl)amino]-2-methyl-2-propanol (133 g). b.p. 100°-108° C. (1.5 mm Hg).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
BuLi (5.2 mL, 1.6M in hexanes) was added to a 0° C. solution of diisopropylamine (0.91 g, 9.0 mmol) in THF (40 mL). The reaction mixture was then stirred at 0° C. for 30 minutes, and then cooled to −78° C. A solution of methyl 3-(4-chlorophenyl)propanoate (1.5 g, 7.5 mmol) in THF (8 mL) was added slowly, and the reaction mixture was stirred at −78° C. for 40 minutes. A solution tert-butyl 2-bromoacetate (4.4 g, 22.7 mmol) in THF (5 mL) was then added. The reaction was then stirred for 30 minutes at −78° C. and then warmed to room temperature and stirred overnight. The reaction was then quenched with saturated NH4Cl and concentrated to remove THF. The reaction was then extracted with EtOAc, and the combined extracts were dried (Na2SO4), filtered, concentrated, and dried in vacuo to give 4-tert-butyl 1-methyl 2-(4-chlorobenzyl)succinate (1.91 g, 81%) as an oil.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[CH3:18][C@H:19]1[O:24][C@@H:23]([CH3:25])[CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:21]2[CH2:20][C@H:19]([CH3:18])[O:24][C@H:23]([CH3:25])[CH2:22]2)[C:14]2[N:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2nc(Cl)nc3c2nc2n3CCOC2(C)C)C[C@H](C)O1
Temperature: 140 °C
Yield: 99.4 %

Procedure:
A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene (100 mg, 0.366 mmol), (2R,6S)-2,6-dimethyl-morpholine (84 mg, 0.732 mmol) and triethylamine (77 μL, 0.55 mmol) in IMS (2 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in cyclohexane) affording 3-Chloro-1-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene as a white solid (128 mg, 99%). LCMS (method A): RT=3.62 min, [M+H]+=352.
Reaction SMILES: [CH3:1][C:2]1[C:11]([F:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:1][Br:17])[C:11]=1[F:12])(=[O:14])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1CBr

Procedure:
30.75 g (0.12 mol) of methyl 2-methyl-3-fluoro-4-methylsulfonylbenzoate were introduced in 600 ml of CCl4. 35.5 g (0.2 mol) of N-bromosuccinimide and 0.86 g (0.002 mol) of benzoyl peroxide were mixed. A third of the amount is added at RT. Then the batch is heated to reflux and “irradiated”. Over the course of an hour the remaining NBS/benzoyl peroxide mixture is added in portions, followed by stirring under reflux for 2 h more. The batch is allowed to cool and is washed with a 10% strength sodium hydrogen sulfite solution, and dried over MgSO4, and the organic phase is concentrated to completion.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[CH:5][N:6]([C:11]5[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=5)[N:7]=4)[CH:3]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:24][CH2:25]1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: CC(=O)c1ccc(-n2cc3cc(N)ccc3n2)cc1
Product: CC(=O)c1ccc(-n2cc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc3n2)cc1

Procedure:
Compound 542 was prepared according to the procedure described in Scheme IV from 5-amino-2-(4-acetylphenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C26H24N4O3: 441.18; found: 441.02.
Reaction SMILES: C(O)C.[C:4]([C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]1[C:16]([CH:17]=[CH:18][CH:19]=[C:20]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N+:15]2[O-])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OS([O-])(=O)=O.[Na+]>O>[C:4]([C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:15]2)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cccc2c1nc1ccc(C(=O)c3ccccc3)cc1[n+]2[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc2c1Nc1ccc(C(=O)c3ccccc3)cc1N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
To a boiled ethanol solution (300 mL) of 7-benzoyl-1-ethoxycarbonylphenazine 5-oxide (4.00 g, 10.7 mmol. obtained in Reference Example 1) was dropwise added for a period of one hour an aqueous solution (150 mL) of 85% sodium hydrosulfate (8.86 g, 43.2 mol.) in gaseous nitrogen atmosphere. After the dropwise addition was complete, the reaction mixture was further heated under reflux for 10 minutes. The refluxed mixture was then cooled to room temperature. To the cooled mixture was added water (150 mL). Thus deposited crystalline product was collected by filtration and washed with water. The washed product was placed under reduced pressure at 40° C. for 16 hours in the presence of diphosphorus pentoxide to dryness. Thus, 3.10 g (81%) of the desired compound was obtained as a brown-violet crystalline product. mp: 175-177° C.