Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,5-Diaminobenzenesulfonamide (Example 17c, 11.16 g, 59.61 mmol) was dissolved in acetonitrile (300 mL) and pyridine (7.07 g, 89.41 mmol) was added. Methanesulfonyl chloride (7.17 g, 62.59 mmol) was added dropwise over a period of 10 min and the reaction mixture was stirred for 16 h at 25° C. after which time a precipitate had formed. Most of the acetonitrile was removed in vacuo and water (200 mL) was added to afford a clear solution. The product slowly started to precipitate and the mixture was placed in an ice bath for 3 h. The precipitate was collected by vacuum filtration and dried under high vacuum to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (also made in Examples 3d and 3d′) (11.1 g, 41.84 mmol, 70.2% yield) as a brown solid. 1H NMR (400 MHz, CD3OD) δ: 2.89 (3H, s), 6.82 (1H, d, J=8.5 Hz), 7.20 (1H, dd, J1=8.5 Hz, J2=2.5 Hz), 7.58 (1H, d, J=2.5 Hz). LC-MS (ESI) calcd for C7H11N3O4S2 265.02, found 266.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:6]2=[O:12].CN(CCN(C)C)C.[I:31]I>C1COCC1>[OH:22][CH:4]1[C:3]2[C:7](=[C:8]([I:31])[CH:9]=[C:10]([Cl:11])[C:2]=2[Cl:1])[C:6](=[O:12])[N:5]1[C:13]([CH3:14])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:21]
Reactant: II
Reactant: CC(C)(c1ccccc1)N1C(=O)c2ccc(Cl)c(Cl)c2C1O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(Cl)c(Cl)c2C1O
Yield: 63.6 %

Procedure:
In a similar manner to Step 3 of Example 16, 4,5-dichloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (400 mg, 1.19 mmol) was dissolved in THF (16 mL), and the solution was treated with TMEDA (0.718 mL, 4.76 mmol), sec-butyl lithium-hexane solution (0.99 mol/L, 4.8 mL, 4.76 mmol) and iodine (453 mg, 1.79 mmol), followed by purification by flash column chromatography (chloroform/methanol=95/5 to 90/10) to obtain 3-hydroxy-4,5-dichloro-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (350 mg, yield 64%).
Reaction SMILES: Cl[C:2]1C=CC(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2CC2)CC)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:38]2[C:46]3[C:41](=[C:42]([CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)([CH:35]2[CH2:37][CH2:36]2)[CH3:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:38]2[C:46]3[C:41](=[C:42]([CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH3:2])=[CH:29][CH:28]=1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Reactant: CCC(c1ccc(Cl)cc1)(c1c[nH]c2c(CSC)cccc12)C1CC1
Product: CCC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 116 mg (0.31 mmol) of the compound from Example 191 in analogy to the synthesis of the compound from Example 209. 98 mg (78% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([C:13](=O)[CH3:14])=[CH:7][CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([CH:13]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:14])=[CH:7][CH:6]=1
Reactant: COc1nc(OCC(F)F)ccc1C(C)=O
Reactant: CC(C)(C)[S@](N)=O
Product: COc1nc(OCC(F)F)ccc1C(C)N[S@](=O)C(C)(C)C
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (400 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone (380 mg, 1.6 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[C:23]([F:28])[CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[C:35]([OH:37])=[O:36])=[CH:4][CH:3]=1.[F:40][C:41]([F:49])([F:48])[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([CH2:17][O:16][C:14]1[CH:13]=[CH:12][C:11]3[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([N:45]5[CH2:46][CH2:47][CH:42]([C:41]([F:49])([F:48])[F:40])[CH2:43][CH2:44]5)=[CH:39][CH:38]=4)[C:8]([C@H:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]4[C:35]([OH:37])=[O:36])=[N:9][C:10]=3[CH:15]=1)[CH:27]=[CH:26]2
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Br)cc1
Reactant: FC(F)(F)C1CCNCC1
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(N2CCC(C(F)(F)F)CC2)cc1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 190 using racemic cis-2-(1-(4-bromobenzyl)-5-((6-fluoroquinolin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and 4-(trifluoromethyl)piperidine. MS (ESI): mass calcd. for C37H36F4N4O3, 660.27; m/z found, 661.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.40 (d, J=8.6, 1H), 8.15-8.08 (m, 1H), 7.78 (d, J=8.6, 1H), 7.69-7.60 (m, 2H), 7.57 (d, J=9.1, 1H), 7.37-7.28 (m, 2H), 7.13-7.02 (m, 4H), 5.68 (d, J=3.9, 2H), 5.49 (s, 2H), 3.82-3.76 (m, 2H), 3.65-3.57 (m, 1H), 2.92-2.88 (m, 1H), 2.88-2.80 (m, 2H), 2.43-2.25 (m, 2H), 2.22-2.15 (m, 1H), 2.05-1.93 (m, 4H), 1.82-1.63 (m, 4H), 1.57-1.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.P(Br)(Br)([Br:17])=O>>[Br:17][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1nc(-c2ccccc2)ncc1Br
Product: Brc1cnc(-c2ccccc2)nc1Br
Temperature: 100 °C
Yield: 62.1 %

Procedure:
A mixture of 5-bromo-2-phenylpyrimidin-4-ol (1.67 g, 6.67 mmol, 1.0 equiv.) and POBr3 (100 g) was heated at 100° C. for 8 hours. The solution was cooled down to 55° C. and poured into ice-water while stirring vigorously. The mixture was maintained below 25° C. during the quench. The reaction mixture was extracted with CH2Cl2. The combined organic layer was washed (cold water), dried (Na2SO4), evaporated and the residue was purified by silica gel chromatography (hexane) to afford 4,5-dibromo-2-phenyl pyrimidine (1.3 g, 70.5%). LC-MS (m/z): 315.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.47-7.50 (m, 3H), 8.37-8.40 (m, 2H), 8.91 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CC(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]2=3)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1ccc2c(c1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOc3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dihydro-2H-benzo[b][1.4]oxazine (0.500 g, 3.70 mmol) and potassium carbonate (2.56 g, 18.5 mmol) in acetone (25 mL) was added 1-(bromomethyl)-4-nitrobenzene (0.959 g, 4.44 mmol). The mixture was heated to reflux and stirred overnight. After 16 hrs the mixture was concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic fraction was dried over Na2SO4, concentrated in vacuo, and the crude residue was purified by silica gel chromatography using 100% Hexanes to 30% Hexanes:EtOAc to afford 4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1.4]oxazine as an orange oil. MS found: M+H+=271.1.
Reaction SMILES: [CH:1]1([C:6]([OH:23])([C:17]#[C:18][Si](C)(C)C)[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-]>CO>[CH:1]1([C:6]([OH:23])([C:17]#[CH:18])[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#C[Si](C)(C)C)C2CCCC2)O1
Agent: [F-]
Solvent: CO
Product: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Yield: 54.5 %

Procedure:
A solution of crude 6-[2-cyclopentyl-2-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl]-2,2-dimethyl-4H-1,3-dioxin-4-one (25 mmol), ceasium fluoride (7.6 g, 50 mmol) dissolved in MeOH (75 mL) was stirred over night. The solvent was removed and the residue was diluted with EtOAc, washed with 0.5 N citric acid, 1 N NaHCO3, brine, dried over MgSO4 and concentrated. Purification by flash column chromatography (20% to 30% EtOAc in hexanes) gave the product (3.6 g, 54%). 1H NMR (300 MHz, CDCl3) □: 1.45-1.80 (m, 8H), 1.72 (s, 3H), 1.74 (s, 3H), 2.13-2.18 (m, 1H), 2.49 (s, 1H), 2.56 (s, 1H), 2.58 (s, 2H), 5.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Br:20][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:17])[C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(Cl)cc2)c(Br)c2ccccc21
Reaction time: 3.5 h

Procedure:
Under an argon atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole (5.0 g, 18.40 mmol) was dissolved in 46 ml of tetrahydrofuran. To this solution was added N-bromosuccinimide (3.28 g, 18.4 mmol of a freshly recrystallized lot), dissolved in 46 ml of tetrahydrofuran. The resulting mixture was stirred over an ice bath for about 3.5 hours, after which time the reaction mixture was poured into about 500 ml of water in which 5.0 grams of sodium sulfate had been dissolved.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.S([CH2:20][N+:21]#[C-:22])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:22][N:21]=[CH:20]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1ccc(-c2cnco2)nc1

Procedure:
In 5.4 ml of methanol was dissolved 200 mg of 5-bromo-2-formyl pyridine (5-bromo-2-pyridinyl aldehyde) which was then reacted with 231 mg of tosylmethylisocyanide for 3 hours in the presence of 178 mg of potassium carbonate under reflux. After completion of the reaction, the same post-treatment as in Preparation Example 13 was carried out to obtain the title compound. 204 mg.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]=1[C:18]([OH:20])=O>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]=1[C:18]([NH:14][CH2:13][CH2:12][CH:2]1[CH2:1][CH2:10][CH2:9][CH2:8][CH2:17]1)=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(Cl)ccc2ncccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCC1CCCCC1)c1c(Cl)ccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.3 mL) was added to a suspension of 6-chloro-5-quinolinecarboxylic acid (example 94(a)) (0.3 g) in dichloromethane and 2 drops of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour then evaporated to an oil. The residue was added to cyclohexylethylamine hydrochloride (0.33 g) and triethylamine (0.6 mL) in dichloromethane and then stirred at room temperature for 1 hour. Water was added and the reaction mixture was extracted with dichloromethane. The combined organics were dried and concentrated. Purification (SiO2, ethyl acetate:isohexane 50:50) gave the sub titled compound as a solid (0.115 g).
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][OH:24]>>[OH:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[NH:16][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15]
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Reactant: NC1CCCCC1CO
Product: O=C(NC1CCCCC1CO)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and 2-amino-cyclohexanemethanol (CAN 89854-92-2) as starting materials, MS (EI): m/e=317.2 [M+H]+.
Reaction SMILES: [C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:13][CH2:12]5)[O:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:35](S(CCCC)=O)[CH2:36][CH2:37]C>>[C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:32][CH2:33]2)[CH2:13][CH2:12]5)[O:8][CH:7]([CH2:35][CH2:36][CH3:37])[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Reactant: CCCCS(=O)CCCC
Product: CCCC1O[C@]23CC[C@@]4(C[C@@H]2[C@@](C)(C(C)(C)C)O1)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5

Procedure:
The title compound 5 was synthesized similar to the procedure described in Example 1 for compound 3 using dibutyl sulfoxide instead of DMSO. After column chromatography, 227 mg (86.3% yield, 99.4 purity) of compound 5 was isolated as an off-white solid as a mixture of two epimers in a 95.4:4.6 ratio.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25](S(C)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][C@H:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25]([NH:44][C@H:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)no3)c2)cc2cnc(S(C)=O)nc21
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](Nc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1)c1ccccc1
Yield: 20.8 %

Procedure:
Using a procedure analogous to Example 57, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.150 g, 0.311 mmol, 1.00 eq) and L-(−)-alpha-methylbenzylamine (0.0846 ml, 0.656 mmol, 3.00 eq) were combined to afford (S)-1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-7-oxo-2-(1-phenylethylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (36 mg, 30% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 8.73 (brs, 1H), 8.65 (brs, 1H), 8.51 (d, J=7.6 Hz, 1H), 8.37 (d, J=7.6 Hz, 1H), 7.85 (s, 1H), 7.44-7.38 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.16 (m, 1H), 6.06 (s, 1H), 5.16-5.09 (m, 1H), 3.48 (s, 3H), 1.48 (d, J=7.2 Hz, 3H), 1.23 (s, 9H); MS (ESI) m/z: 556.3(M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1.CCO>[OH:16][B:15]([OH:17])[C:12]1[CH:13]=[CH:14][C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][OH:20])=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-benzoyl phenyl boronic acid (226.00 mg, 1.00 mmol) and hydroxylamine hydrochloride (84.00 mg, 1.20 mmol) in pyridine (5 mL) and EtOH (5 mL) was refluxed at 125° C. for 24 h. Reaction was then concentrated in vacuo to give a crude product which was used for next step without further purification. MS (ES+): m/z 241.89 (100)[MH+]. HPLC: tR=2.56 min (Open Lynx polar—5 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:20][C:21]1[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1>C1COCC1>[NH2:20][C:21]1[CH:28]=[C:27]([O:9][CH2:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN1CCC(CO)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(COc2cc(N)ncc2C#N)CC1
Reaction time: 0.03 h

Procedure:
(1-methylpiperidin-4-yl)methanol (283 mg, 2.19 mmol) was treated at room temperature with KHMDS (1 M in THF, 2.0 ml, 2.0 mmol). The reaction mixture was stirred for 2 min and then added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 100 mg, 0.729 mmol) in THF (1 ml). The resulting dark brown solution was stirred at room temperature for 1 h, quenched with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified twice by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(1 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a light brown resin. (UPLC-MS 3) tR 0.31 min, 0.33 min; ESI-MS 247.2, 247.2 [M+H]+.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].CS[C:8]1[N:9]([CH3:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[N+:12]=1[CH3:13].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:8]1[N:9]([CH3:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[N+:12]=1[CH3:13]
Reactant: C1CCNCC1
Reactant: CSc1n(C)c2ccccc2[n+]1C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c(C2CCCCN2)[n+](C)c2ccccc21

Procedure:
Heat 0.01 mol of 2-methylmercapto-1,3-dimethylbenzimidazolium perchlorate with 0.01 mol of piperidine for 4 h at reflux in 250 ml of dioxane. Remove the solids by suction and recrystallise from ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8]([C:22]([F:25])([F:24])[F:23])([O:17][Si](C)(C)C)[C:9]=1[NH:10]2.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8]([C:22]([F:25])([F:23])[F:24])([OH:17])[C:9]=1[NH:10]2
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCc2c1[nH]c1cc(Cl)c(Cl)c(Cl)c21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1cc(Cl)c(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
5,6,7-Trichloro-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.11 g, 0.25 mmol) was dissolved in THF (5 mL) and a solution of KOH (0.050 g, 1 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 1 h, diluted with water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography [EtOAc-hexane (1:9) as eluant] to furnish the title compound (0.09 g, 44%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.28 (bs, 1H), 7.42 (s, 1H), 3.29-3.23 (m, 1H), 3.02-2.95 (m, 1H), 2.44 (s, 1H), 2.26-2.22 (m, 1H), 2.09-1.98 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[NH:25][N:24]=NN=2)[CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[C:4]([C:21]2[O:28][C:26]([CH3:27])=[N:24][N:25]=2)[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(Br)cc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(C)o4)cc(Br)cc32)cc1
Temperature: 130 °C
Yield: 28.1 %

Procedure:
A stirred mixture of 6-Bromo-1-[(4-methylphenyl)sulphonyl]-4-(1H-tetrazol-5-yl)-1H-indazole (300 mg, 0.615 mmol) and acetyl chloride (0.722 ml, 10.15 mmol) in toluene (10 ml) were heated under microwave irradiation at 130° C. for 20 mins. The reaction mixture was heated for a further 20 mins at 130° C. then evaporated to dryness. The resultant yellow solid was treated with methanol (10 ml), to give a beige solid and supernatant. The supernatant was pipetted off, the process repeated twice and the resultant solid dried under vacuum to give the title compound as a beige solid (75 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1([C@H:13]2[CH2:17][CH2:16][N:15]([C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:14]2=O)[CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][N:15]([C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14]2)[CH2:11][CH2:12]1)[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1CC[C@H](C2(N(C)C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@@H](C2(N(C)C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one (7.53 g, 21.0 mmol) was dissolved in anhydrous tetrahydrofuran (70 ml) and a 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (63.0 ml, 63.0 mmol) was added dropwise gradually thereto while stirring and cooling with ice. After completion of dripping, it was stirred at room temperature for 20 hours. After slowly adding an aqueous solution (72 ml) of potassium carbonate (7.22 g) while cooling with ice, it was heated under reflux for 1.5 hours. After letting the reaction solution cool to room temperature, water (150 ml) was added, extraction with ethyl acetate (200 ml×2) was performed, and then the combined organic layer was washed with saturated saline solution (200 ml) and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 7.19 g (99%) of the title compound was obtained in the form of a colorless syrup from a chloroform:methanol=50:1 eluate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:11](=[O:10])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C#N)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(CNC(=O)OC(C)(C)C)n1
Reaction time: 24 h

Procedure:
To a solution of 6-methyl-2-cyanopyridine (5 g) and BOC2O in EtOAc was added 10% Pd/C. The reaction mixture was stirred under a balloon of H2 for 24 h, and then filtered through diatomaceous earth and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a colorless oil. 1H NMR (d6-DMSO, 400 MHz) δ 7.6 (t, 1H), 7.4 (br s, NH), 7.2 (d, 1H), 7.1 (d, 1H), 4.2 (d, 2H), 2.4 (s, 3H), 1.4 (s, 9H).