Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][C@H:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:16]3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>O1CCCC1.C(OC)(C)(C)C.Cl>[C:24]1([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C@@H:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH:14]=2)[O:19]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H](c2ccccc2C)O3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1ccccc1[C@@H]1CCc2cc(O[C@H]3CC[C@H](C(=O)O)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.75 g (1.9 mmol) of trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester was dissolved in 10 ml of tetrahydrofuran. 94 mg (3.9 mmol) lithium hydroxide (dissolved in 2 ml of water) were added. The solution was stirred at room temperature overnight until no starting material could be detected by RP-HPLC. The solution was diluted with methyl tert-butyl ether, and 2N hydrochloric acid was added until a pH of 2. After phase separation, the organic layer was dried over magnesium sulfate and the solvent was evaporated. The resulting product crystallized on standing to yield 0.65 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)=[CH:5][CH:4]=1.[C:29](O)(=[O:32])[CH:30]=[CH2:31]>>[O:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:12]3[N:11]=[C:10]([S:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:8][CH:7]=4)[CH:15]=[CH:14][N:13]=3)=[CH:18][CH:19]=2)[CH2:28][CH2:27]1
Reactant: NCc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: C=CC(=O)O
Product: C=CC(=O)NCc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Yield: 27.3 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(4-(aminomethyl)phenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (70 mg, 0.18 mmol) and acrylic acid (19 mg, 0.27 mmol) furnished the product (22 mg, 27%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C:7](Cl)=[O:8])[CH2:4][O:3]1.Cl.[S:12]1[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]2[O:23][C:22](=[O:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH:32]=4)=[C:27]([F:37])[CH:26]=3)[CH2:20]2)=[N:13]1.N1C=CC=CC=1>ClCCl>[S:12]1[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]2[O:23][C:22](=[O:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:36][CH2:35][N:34]([C:7]([C@H:5]5[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]5)=[O:8])[CH2:33][CH:32]=4)=[C:27]([F:37])[CH:26]=3)[CH2:20]2)=[N:13]1
Reactant: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CC1(C)OC[C@H](C(=O)Cl)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC[C@H](C(=O)N2CC=C(c3ccc(N4C[C@H](COc5cnsn5)OC4=O)cc3F)CC2)O1
Yield: 92.5 %

Procedure:
A solution of (R)-2,2-dimethyl-1,3-dioxolan-4-ylcarbonyl chloride (S Handa et al, Synth. Commun. (1995), 25, 2837) [0.597 g, 3.63 mmol ] in dichloromethane (5 ml) was added dropwise to a stirred mixture of 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one hydrochloride (1 g, 2.42 mmol) and pyridine (0.49 ml, 6.06 mmol) in dichloromethane (30 ml) under nitrogen at −10° C. After 10 minutes the cooling bath was removed and the mixture stirred for a further hour. Water (30 ml) was added and the organic layer washed with brine, dried (Na2SO4) and evaporated. The residue was triturated with ether and filtered to give 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one as a solid (1.13 g, 93%) MS: 504 (MH+); NMR: 1.32 (6H, s); 2.42 (2H+DMSO); 3.7 (2H, m); 4.0 (1H, m); 4.11 (2H, m); 4.25 (2H, m); 4.8 (2H, m); 4.91 (1H, m); 5.12 (1H, m); 6.02 (1H, s); 7.29-7.43 (2H, m); 7.5 (1H, d); 8.42 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[NH4+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
4-Chloroquinoline (5 g, 31 mmol) was dissolved in sulfuric acid (23 mL, 0.42 mol), to which nitric acid (4.5 mL, 0.11 mol) was slowly added dropwise, which was then stirred at room temperature for four hours. When the reaction was completed, the resultant was cooled to 0° C., and neutralized with 1M ammonium hydroxide. The generated solid was dissolved in ethyl acetate, dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=⅓) to obtain 3.55 g of the desired compound as a white solid (yield 55.7%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:21])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1.[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29])(=[O:25])=[O:24]>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH:3]([OH:21])[CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]1
Reactant: NCC(O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Product: CS(=O)(=O)c1ccccc1C(=O)NCC(O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
Prepared as described in Example 1 from 1-amino-4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.2 g) and 2-(methylsulphonyl)benzoic acid (0.12 g). Title compound obtained as white solid (0.090 g).
Reaction SMILES: C([Li])CCC.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[CH3:11][C@:12]12[C:18]([CH3:20])([CH3:19])[C@:15]([C:21]([N:23](C([C@@]34C(C)(C)[C@@](C)(CC3)C(=O)O4)=O)[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:22])([CH2:16][CH2:17]1)[O:14][C:13]2=[O:50]>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([C@@:15]23[C:18]([CH3:19])([CH3:20])[C@@:12]([CH3:11])([CH2:17][CH2:16]2)[C:13](=[O:50])[O:14]3)=[O:22])=[C:25]([C@@:31]([OH:36])([C:10]#[C:9][CH:6]2[CH2:8][CH2:7]2)[C:32]([F:33])([F:34])[F:35])[CH:26]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)N(C(=O)[C@@]13CC[C@@](C)(C(=O)O1)C3(C)C)c1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Reactant: C#CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Reaction time: 1 h

Procedure:
2.5M n-Butyllithium (2.05 mL, 5.14 mmol) was added slowly to a solution of cyclopropyl acetylene (0.34 g, 5.14 mmol) in tetrahydrofuran (4 mL) in an ice-salt-bath under argon, and then N,N-bis((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl)-4-chloro-2-(2,2,2-trifluoroacetyl)aniline (11, 1 g, 1.71 mmol) in THF (2 mL) was added. The reaction mixture was stirred for 1 hour. The reaction was quenched with 10% citric acid aqueous, the mixture was extracted with ethyl acetate and the two layers were separated. The organic layer was evaporated to dryness to give a crude oil and further crystallized with ethyl acetate and petroleum ether to give pure (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=O)([CH3:7])[CH3:6])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=[C:24]1[C:23]2[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)[NH:26][C:25]1=[O:29])([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)Nc2cc(Cl)ccc21
Yield: 77.9 %

Procedure:
In a manner similar to the method described in Example 227b, 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) was reacted with 6-chlorooxindole (3.6 g, 22 mmol) and pyrrolidine (1.85 g, 26 mmol) in methanol to give E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH2:34][C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=1
Reactant: O=C(CS(=O)(=O)c1ccccc1Br)N1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CC(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-1-morpholinoethanone. MS (ESI): mass calcd. for C22H21FN4O4S, 456.5; m/z found, 457.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=1.4, 2H), 8.15 (dd, J=7.7, 1.3, 1H), 7.83-7.72 (m, 1H), 7.72-7.63 (m, 1H), 7.58 (dd, J=8.5, 7.7, 1H), 7.45 (dd, J=7.2, 1.2, 1H), 7.42-7.31 (m, 2H), 3.67-3.55 (m, 4H), 3.48 (t, J=4.8, 2H), 3.39 (t, J=4.8, 2H).
Reaction SMILES: [CH2:1]([C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:36]>O>[CH2:1]([C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].[Na+:36]
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A suspension of the product of Example 33C (0.054 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.108 mL, 0.107 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.052 g, 93%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.57 (m, 1 H) 0.68 (m, 3 H) 0.87 (m, 1 H) 1.06 (m, 2 H) 1.38 (m, 3 H) 1.71 (m, 1 H) 2.13 (m, 1 H) 2.95 (m, 3 H) 7.31 (m, 3 H) 7.46 (m, 3 H) 8.05 (m, 1 H) 9.86 (m, 1 H) 15.48 (m, 1 H). MS (ESI−) m/z 502 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:36])=[C:25]([CH:27]=[N:28][C:29]([O:31][Si](C)(C)C)=[CH2:30])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[CH2:30][C:29](=[O:31])[NH:28][CH:27]([C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[CH3:36])[C:5]32[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][C:6]3=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccc(F)cc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1ccc(F)cc12
Yield: 41 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-5-fluoro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 170b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-5-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 2 g, 41%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[C:9]([O:8][C:7](=[O:13])[NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:2]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(S(N)(=O)=O)C1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3R)-pyrrolidin-3-ylcarbamate (1.3 g) in dioxane (50 ml) was added sulfamide (1.55 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.69 g
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)[Cl:5].[CH2:9]([O:16][NH:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[N:35]=[CH:34][O:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([O:16][N:17]([C:4]([Cl:5])=[O:3])[C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[N:35]=[CH:34][O:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncon1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1ncon1
Reaction time: 3 h
Yield: 183.1 %

Procedure:
TEA (405 mg, 4.0 mmol) and diphosgene (514 mg, 2.6 mmol) were added to a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (750 mg, 2.0 mmol) in DCM (70 mL). The mixture was stiffed at 0° C. for 3 hrs. Then, the reaction mixture was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to give (2S,5R)-tert-butyl 5-(benzyloxy(chlorocarbonyl)amino)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.6 g), which was used directly in the next step. ESI-MS (EI+, m/z): 437[M+H]+.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](O)[C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([NH:32][C:33](=[O:49])[C:34]4[C:39]([F:40])=[CH:38][CH:37]=[C:36]([NH:41][S:42]([CH2:45][CH2:46][CH3:47])(=[O:44])=[O:43])[C:35]=4[F:48])[CH:30]=3)[NH:25][CH:24]=2)=[CH:18][CH:17]=1>CC#N>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([NH:32][C:33](=[O:49])[C:34]4[C:39]([F:40])=[CH:38][CH:37]=[C:36]([NH:41][S:42]([CH2:45][CH2:46][CH3:47])(=[O:44])=[O:43])[C:35]=4[F:48])[CH:30]=3)[NH:25][CH:24]=2)=[CH:20][CH:21]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(O)c4ccc(Cl)cc4)c3c2)c1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(Cc4ccc(Cl)cc4)c3c2)c1F
Temperature: 80 °C
Yield: 85.6 %

Procedure:
Triethylsilane (0.0590 mL, 0.355 mmol) and trifluoroacetic acid (“TFA”; 0.0180 mL, 0.234 mmol) were added to N-(3-((4-chlorophenyl)(hydroxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.009 mmol) in CH3CN (1 mL). The solution was warmed to 80° C. for 10 minutes. The solution was cooled and concentrated under reduced pressure to provide N-(3-(4-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (4 mg, 82.5%). 1H NMR (400 MHz, CD3OD) δ 8.63-8.44 (m, 1H), 8.30-8.32 (m, 1H), 7.62-7.68 (m, 1H), 7.35 (s, 1H), 7.27 (s, 4H), 7.10-7.15 (m, 1H), 4.11 (s, 2H), 3.09-3.13 (m, 2H), 1.84-1.89 (m, 2H), 1.03-1.07 (m, 3H); m/z (APCI-pos) M+1=519.1.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=O)[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=[S:34])[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (iv) (0.53 g) and Lawesson's reagent (0.675 g) according to the method of example 2 step (ii). Purification was by chromatography eluting with 50% acetone in iso-hexane followed by trituration with acetonitrile.
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][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F
Yield: 65 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2-fluoro-phenylhydrazine according to the method described for Example 1 in 65% yield. MS: M=417.0 (M+H)+
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])[CH:2]=1.[H-].[Na+].[CH3:20]I>C1(C)C=CC=CC=1>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([CH3:20])[C:9](=[O:11])[CH3:10])[CH:2]=1
Reactant: CC(=O)NCc1cccc(-c2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)N(C)Cc1cccc(-c2ccccc2)c1
Reaction time: 8 h
Yield: 107.8 %

Procedure:
N-biphenyl-3-ylmethyl-acetamide (860 mg, 3.8 mmol) was dissolved in 10 mL of toluene. To this was added 611 mg of 60% NaH (mineral oil) and MeI (0.48 mL, 7.6 mmol). The resulting mixture was stirred overnight then filtered. The solvent was removed under vacuum to yield 980 mg (108% yield) of N-biphenyl-3-ylmethyl-N-methyl-acetamide. HRMS ((M+H) calcd for C16H18N): 240.1389; found: 240.1398. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 2.17 (s), 2.19 (s), 2.96 (s), 2.99 (s), 4.60 (s), 4.66 (s), 7.15-7.60 (overlapping m). 13C NMR (125 MHz, CDCl3) δ: 21.55, 21.91, 33.84, 35.61, 50.66, 54.33, 125.05, 125.16, 126.25, 126.55, 126.85, 127.00, 127.20, 127.23, 127.42, 127.65, 128.79, 128.90, 129.06, 129.45, 137.19, 137.95, 140.65, 140.95, 141.64, 142.12, 170.79, 171.08.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:13]/[C:14](/[C:17]([CH3:19])=O)=[N:15]\[OH:16].[ClH:20].COC(C)(C)C>C(O)(=O)C>[ClH:20].[CH3:13][C:14]1[N+:15]([O-:16])=[C:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][C:17]=1[CH3:19]
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 10 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Into a solution of 4-trifluoromethyl benzaldehyde (400.0 g, 2.3 mol) and 2,3-butanedione monoxime (212 g, 2.055 mol) in 800 mL of glacial acetic acid at 2–5° C., hydrogenchloride gas (250 g) is slowly bubbled for 1.5 hours. The mixture is stirred at the same temperature for 1 hour further. 3.75 L of t-butyl methyl ether are added while maintaining the temperature between 5–25° C. (first 400 mL addition is exothermic). The resulting suspension is stirred for 30 minutes, then cooled to 10° C. and the solids are collected by filtration. The filter cake is washed with 500 mL of t-butylmethyl ether, and dried at 55–60° C. (20 mbar) for 18 hours to afford 550 g (91% yield) of 4,5-dimethyl-2-[4-(trifluoromethyl)phenyl]-oxazole 3-oxide, hydrochloride salt: m.p. 182–184° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2.[CH3:14][O-:15].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: Nc1nc2cc(F)ccc2nc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2ccc(F)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To 3-amino-2-chloro-6-fluoroquinoxaline (550 mg, 2.78 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (6.01 g, 27.8 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 491 mg of the titled compound (yield, 91%).
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>>[CH:1]1([C:7](=[S:19])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CCCCC1
Product: NC(=S)C1CCCCC1

Procedure:
Following Method 3, cyclohexanecarboxamide and Lawesson's reagent were reacted, yielding cyclohexanecarbothioamide. LCMS (m/z): 144.1 (MH+); LC Rt=5.10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:34]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 39 mg (32%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.30 (br s, 1H, NH), 11.69 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.8 & 6.7 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.43 (m, 1H), 7.41 (s, 1H), 7.35 (t, J=9 Hz, 1H), 3.59 (m, 4H, 2×CH2), 3.51 (m, 4H, 2×CH2), 2.21 (s, 3H, CH2). MS 483 [M++1].