Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[NH2:14][OH:15]>C(O)C>[Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)c2ncccc12
Solvent: CCO
Product: ON=Cc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 8-bromo-5-quinolinecarboxaldehyde (i.e. the product from Step B) (1.7 g, 7.1 mmol) in ethanol (30 mL) was added an aqueous solution of hydroxylamine (0.7 mL, 50% in water). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to provide the title compound as a pale yellow solid (1.8 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[S:18])[NH2:17])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.Cl[CH2:24][C:25]([CH2:27]Cl)=O.C(=O)([O-])[O-:30].[Na+].[Na+]>C(O)(C)C.O>[CH:24]([C:25]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:19]([F:22])([F:20])[F:21])=[N:5]3)[CH2:11][CH2:12]2)[S:18][CH:27]=1)=[O:30]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CCl)CCl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1

Procedure:
To a mixture of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbothioamide (i.e. the product of Example 1, Step C) (20 g, 59.9 mmol) in isopropyl alcohol (90 mL) was added 1,3-dichloroacetone (8.99 g, 71.3 mmol) and the reaction mixture heated at 65 for 1.5 h. After cooling, a solution of sodium carbonate (7.39 g, 70.0 mmol) in water (92 mL) was added dropwise. After 2 h additional water (31 mL) was added and the resulting precipitate rinsed with water (62 mL). Drying overnight under reduced pressure at 45° C. provided 18.24 g of the title compound as a light gray solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:19]3[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([F:35])[CH:22]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:19]3[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:35])[CH:22]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(Cc2cc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)c3c(N)ncnn23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)N1CCN(Cc2cc(-c3ccc(N)c(F)c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
To a solution of t-butyl (4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)carbamate (320 mg, 0.62 mmol) in CH2Cl2 (8 ml) was added TFA (3 ml) and was stirred at rt for 3 h. The reaction mixture was partially evaporated and was added 10 ml ethyl acetate and washed with saturated aq. NaHCO3. The organic was dried over Na2SO4, concentrated and purified via column chromatography (95:5, v/v, CH2Cl2—CH3OH) to afford 74 mg of the title compound (yield 30%). 1H-NMR (CH3OH-d4) δ 7.85 (s, 1H), 7.10 to 7.00 (m, 3H), 6.66 (s, 1H), 4.00(s, 2H), 3.60 to 3.50(m, 4H), 2.63 to 2.55(m, 4H), 20.6(s, 3H); MS [M+H]+=383.9; LCMS RT=1.10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:25])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)O)c2)c2ccc(Cl)cc2F)ccc1=O
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2cccc(C(=O)N3CCOCC3)c2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 320, step 4) was coupled with morpholine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=483.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[CH3:28][NH2:29]>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:29][CH3:28])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CN
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (e.g. the cyanobenzoxazinone product of Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (52 mg), which decomposed in the melting apparatus above 140° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1S[C:11]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:10]=2[CH:9]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[CH2:8]1.OO.[O-][S:28]([O-:30])=[O:29].[Na+].[Na+]>CCOC(C)=O.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1[S:28](=[O:30])(=[O:29])[C:11]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:10]=2[CH:9]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[CH2:8]1
Reactant: O=S([O-])[O-]
Reactant: CCC(=O)NC1CC(COCCOC)Sc2sc(S(N)(=O)=O)cc21
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)NC1CC(COCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
To a solution of 10 (37.3 g, 0.095 mol) in EtOAc (1 l ) under N2 stirred at r.t. was added NaWO4 ·2H2O (2.9 g, 0.009 mol) in H2O (45 mol). After 15 min., 30% H2O2 (27 ml, 0.26 mol) was added dropwise. After addition, the solution was heated at 40° C. After 3.5 h, Na2SO3 (12 g, 0.095 mol) in H2O (12.5 ml) was added until a negative starch iodide test was observed. The layers were separated, extracted with EtOAc (1×) and the organic layers were washed with saturated NaCl, dried, filtered and concentrated to dryness to yield 39.9 g (98%) of 11.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[O:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([O:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid methyl ester (395 mg, 1.14 mmol) in ethanol (15 mL) at 25° C. was treated with a solution of potassium hydroxide (320 mg, 5.69 mmol) in water (3 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water and evaporated under reduced pressure. The concentrate was acidified to pH 2 with an aqueous solution of 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated in vacuo. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) to furnish rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid (364 mg, 96% yield) as a colorless oil: EI-HRMS m/e calcd for C14H17ClSO5 (M+) 332.0485, found 332.0486.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=1>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[C:36]([F:39])([F:37])[F:38])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4 g, 18.6 mmol) was dissolved in 200 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (9 mL, 111 mmol) followed by the dropwise addition of oxalyl chloride (4.8 mL, 54 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off white oil. Redissolved (2 g, 8.5 mmol) oil in 40 mL dry DCM under Ar, cooled to 0° C., added 2.8 mL pyridine followed by 4-bromo-2-trifluoromethylaniline (2.05 g, 8.6 mmol). The reaction was allowed to warm to ambient temperature, stirred overnight then concentrated. Redissolved in 100 mL EtOAc, washed with 1 N HCl (3×50 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound. (1.98 g, 53%) APCI (AP−): 435.0, 437.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:58][CH2:57][C@@:56]([F:62])([C:59](O)=[O:60])[CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[F:62][C@@:56]1([C:59](=[O:60])[NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])[CH2:57][CH2:58][N:54]([C:52]([O:51][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:53])[CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Yield: 37.9 %

Procedure:
According to the general procedure D, from #86 (300 mg, 0.45 mmol, 1 eq.), #169 (106 mg, 0.45 mmol, 1 eq.), dichloromethane (10 mL), HATU (194 mg, 0.54 mmol, 1.2 eq.) and diisopropylethylamine (117 mg, 0.9 mmol, 2 eq.) was synthesized the crude desired material, which was purified by reverse phase chromatography (Method P) to afford #193 (149 mg, 37%) as a white solid. HPLC (Protocol X): m/z 873.4 [M+H+], retention time=3.34 minutes (purity=98%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[CH3:6][C:7]1([CH3:14])[CH2:12]C[C:10](=[O:13])[CH2:9][CH2:8]1.C(OCC)=O>C(OCC)C>[OH:5]/[CH:3]=[C:4]1\[C:10](=[O:13])[CH2:9][CH2:8][C:7]([CH3:14])([CH3:12])[CH2:6]\1
Reactant: CCO
Reactant: CC1(C)CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Product: CC1(C)CCC(=O)/C(=C\O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 818.5 %

Procedure:
A dry round-bottomed flask was charged with sodium hydride (60% dispersion in mineral oil, 475 mg, 11.9 mmol) and diethyl ether (24 ml). The reaction was cooled to 0° C. and ethanol (0.06 ml, 1.03 mmol) was added dropwise. The suspension was stirred for at 0° C. for 20 min then a solution of 4,4-dimethylcyclohexanone (1.50 g, 11.9 mmol) and ethyl formate (1.45 ml, 17.8 mmol) in diethyl ether (3 ml) was added dropwise over 15 min. The yellow solution was stirred at 0° C. for 3 h then slowly allowed to warm to room temperature overnight. Ethanol (0.24 ml) was added and the mixture was stirred at room temperature for 1 h then quenched with water and extracted with diethyl ether. The aqueous layer was acidified with 6M HCl until pH=2 then extracted with diethyl ether (2×). The combined organic layers were washed with brine then dried over sodium sulfate, filtered and concentrated to give 1.30 g (71%) of 2-[1-hydroxy-meth-(Z)-ylidene]-4,4-dimethyl-cyclohexanone as a pale brown oil which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm) 14.40 (br. s., 1H), 8.58 (s, 1H), 2.39 (t, J=6.8 Hz, 2H), 2.13 (s, 2H), 1.48 (t, J=6.8 Hz, 2H), 1.00 (s, 6H).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3([C:26]4[CH:25]=[C:24](I)[CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:4]=2[CH:3]=1.[C:28]1([N:34]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].C(P([C:65]([CH3:68])([CH3:67])C)C(C)(C)C)(C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:31]1[CH:32]=[CH:33][C:28]([N:34]([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:14]=[CH:13][C:12]4[C:11]5[C:6]([C:5]6([C:26]7[CH:25]=[C:24]([C:38]8[CH:39]=[CH:40][C:35]([N:34]([C:67]9[CH:65]=[CH:68][CH:49]=[CH:44][CH:45]=9)[C:28]9[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=9)=[CH:36][CH:37]=8)[CH:23]=[CH:22][C:21]=7[C:20]7[C:15]6=[CH:16][CH:17]=[CH:18][CH:19]=7)[C:4]=4[CH:3]=3)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[CH:37][CH:36]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:29][CH:30]=1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Ic1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(I)cc21
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc4c(c3)C3(c5ccccc5-4)c4ccccc4-c4ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)cc43)cc2)cc1
Yield: 597.8 %

Procedure:
2,2′-Diiodo-9,9′-spirobifluorene (2.84 g, 5.0 mmol), 4-(diphenylamino)phenylboronic acid (4.34 g, 15.0 mmol), Pd(PPh3)4 (0.289 g, 0.25 mmol), 2M K2CO3(aq) (25 ml) and tri-tert-butylphosphine (0.5 mmol) were mixed in a flask containing with toluene (50.0 mL). The mixture was refluxed 72 hours. The solution was extracted twice with chloroform. The combined organic extracts were dried (MgSO4) and concentrated by rotary evaporation. Column chromatography on silica gel (hexane/chloroform=3/1) afforded products as white solids 22DPASF (2.4 g, 60%).
Reaction SMILES: N[CH2:2]C1C2C(=C(OC)C([Br:12])=CC=2)CC1.[Br:15][C:16]1[CH2:17][CH2:18][CH:19]2[C:28]3[C:27]=1[C:26]([O:29][CH3:30])=[CH:25][N:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][C:22]=3[CH2:21][CH2:20]2.C(O)=O.C=O>>[BrH:12].[Br:15][C:16]1[CH2:17][CH2:18][C@@H:19]2[C:28]3[C:27]=1[C:26]([O:29][CH3:30])=[CH:25][N:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:23][C:22]=3[C@H:21]([CH3:2])[CH2:20]2
Reactant: COC1=CN(c2ccccc2)CC2=C3C1=C(Br)CCC3CC2
Reactant: COc1c(Br)ccc2c1CCC2CN
Agent: C=O
Solvent: O=CO
Product: Br
Product: COC1=CN(c2ccccc2)CC2=C3C1=C(Br)CC[C@H]3C[C@H]2C

Procedure:
Using the methods described above and starting with 1-aminomethyl-5-bromo-4-methoxyindan, 7-bromo-6-methoxy-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine is prepared. This intermediate is N-methylated using formic acid-formaldehyde to give cis, trans-7-bromo-6-methoxy-2-methyl-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine hydrobromide and, after demethylation using boron tribromide, cis or trans-7-bromo-6-hydroxy-2-methyl-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.O.ON1C2C=CC=CC=2N=N1.[CH:26]1([N:32]=[C:33]=NC2CCCCC2)CCC[CH2:28][CH2:27]1.CNCCC>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:32]([CH3:33])[CH2:26][CH2:27][CH3:28])=[O:9])[CH:5]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCCNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 0 °C

Procedure:
Dissolve 5-iodo-isophthalic acid monomethyl ester (9.34 g, 30.5 mmol), 1-hydroxybenzotriazole hydrate (4.86 g, 36 mmol) and a solution of 1,3-dicyclohexylcarbodiimide (1 M in dichloromethane; 36 mL) in THF (70 mL). Cool to 0° C. for 15 min. Add methylpropylamine (3.69 mL, 36 mmol) and stir at room temperature for 12 h. Filter the solution though a filtering agent and wash with ethyl acetate, concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[S:20])[CH3:17]>C(OC(C)C)(C)C>[ClH:1].[CH2:22]([N:21]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:20][C:19]1=[N:18][CH2:16][CH3:17])[CH3:23]
Reactant: Cc1ccc(C(=O)CCl)cc1S(N)(=O)=O
Reactant: CCNC(=S)NCC
Solvent: CC(C)OC(C)C
Product: CCN=C1SCC(O)(c2ccc(C)c(S(N)(=O)=O)c2)N1CC
Product: Cl

Procedure:
5 g of 2-chloro-4'-methyl-3'-sulfamoylacetophenone and 2.7 g of 1,3-diethylthiourea were reacted as prescribed in Example 12. After addition of 200 ml of diisopropyl ether the solvent was decanted and the oily end product was crystallized under ethyl acetate heated to 40° to 50° C. Colorless solid body, melting point: 160° C (decomposition).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][CH3:31])[N:19]=2)=[C:9]1[CH3:32])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:30]([N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:33])=[O:5])[C:9]=2[CH3:32])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])[CH3:31]
Reactant: CCN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1N=C(c2c(C)n(CC(=O)O)c3ccc(F)cc23)c2ccccc2S1(=O)=O

Procedure:
[3-(2-Ethyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4yl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.09 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H), 7.48 (d, 1H), 7.42 (dd, 1H), 6.97 (m, 2H), 4.52 (s, 2H), 3.96 (q, 2H), 2.21 (s, 3H), 1.39 (t, 3H) ppm. MS calculated for C20H18FN3O4S—H: 414, observed: 414.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([CH:22]2[CH2:24][CH2:23]2)[C:20]2[C:25]([C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl.CO>[NH2:14][C@H:15]([C:17]1[N:21]([CH:22]2[CH2:23][CH2:24]2)[C:20]2[C:25]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[N:18]=1)[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
TFA (1 mL) was added to a stirring solution of {(S)-1-[1-cyclopropyl-6-fluoro-7-(morpholine-4-carbonyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (380 mg, 0.88 mmol) in DCM (3 mL). After stirring at RT for 2 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (214 mg, 73%). LCMS (Method B): RT 1.62 and 1.70 min [M+H]+ 333.12
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1.Cl>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1
Yield: 51 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 3-chloro-phenylhydrazine×HCl according to the method described for Example 1 in 51% yield. MS: M=417.4 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[CH:4][N:3]=1.CO[C:13](OC)(OC)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:10][N:9]1[C:7](=[S:8])[N:6]2[N:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: CNC(=S)n1ncnc1N
Product: Cn1c(-c2ccccc2)nc2ncnn2c1=S
Yield: 66 %

Procedure:
The synthesis method of Example 96 was applied. The compound (1.50 g) obtained in Example 29 and trimethylorthobenzoate (5.0 ml) were used. The mixture was reacted at 150° C. for 2 hours. The resulting crystals were collected by filtration and purified by a method similar to the method of Example 98, whereby crystals (1.53 mg) were obtained (yield 66%). The crystals were recrystallized from methanol to give colorless transparent plate crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][S:4][N:3]=1
Reactant: Sc1ccccc1
Reactant: O=c1c(Cl)nsnc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=c1c(Cl)nsnc1Sc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 3.66 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one, 30 ml of ethyl ether, and 2.02 g of triethylamine is stirred at 0°-5° C. while a solution of 2.20 g of thiophenol in 20 ml of ethyl ether is added dropwise to it. This mixture is stirred 2 hours longer while it is allowed to return to ambient temperature. Then it is filtered to remove triethylamine hydrochloride, and the filtrate is concentrated on a rotary evaporator. The solid residue is recrystallized from hexane to yield yellow prisms, mp 100°-2°.