Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:25][C:26]1([CH3:51])[CH:35]=[C:34]([CH3:36])[C:33]2[N:32]=[CH:31][N:30]=[C:29]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)[C:28]=2[CH2:27]1>>[NH2:16][C@@H:13]1[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:29]5[C:28]6[CH2:27][C:26]([CH3:25])([CH3:51])[CH:35]=[C:34]([CH3:36])[C:33]=6[N:32]=[CH:31][N:30]=5)[CH2:43][C:42]=4[CH:44]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(B(O)O)cc2C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Product: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(-c3cnc(N)c(S(=O)(=O)N4CC[C@@H](N)C4)c3)cc2C1

Procedure:
Synthesized according to the method of example 5 using (R)-tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)pyrrolidin-3-ylcarbamate (reagent preparation 25) and [4-(6,6,8-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 and BOC group deprotection. 1H NMR (400 MHz, d6-DMSO): 8.54 (s, 1H), 8.48 (br s, 1H), 8.01 (d, 1H), 8.58 (d, 1H), 7.47 (dd, 1H), 7.02 (d, 1H), 6.76 (br s, 2H), 5.99 (d, 1H), 4.60 (s, 2H), 4.32 (m, 2H), 383 (m, 2H), 3.40-3.32 (m, 4H), 3.30-3.26 (m, 2H), 2.90 (m, 1H), 2.70 (s, 2H), 1.97 (s, 3H), 1.89 (s, 6H), 1.63 (m, 1H), 0.93 (s, 6H); MS (EI) for C29H35N7O3S: 562 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C(N(CC)C(C)C)(C)C.[C:22]([O:25][CH2:26]Br)(=[O:24])[CH3:23].CCC(OBr)=O>C(#N)C>[C:22]([O:25][CH2:26][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])(=[O:24])[CH3:23]
Reactant: CC(=O)OCBr
Reactant: O=C(O)Cc1ccc(I)cc1F
Agent: CCC(=O)OBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCOC(=O)Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 2-fluoro-4-iodo phenyl acetic acid (described in U.S. Pat. No. 6,252,090, incorporated herein by reference;, 0.82 g, 2.93 mmol) in anhydrous acetonitrile (10 mL) was treated with N,N-diisopropyl ethyl amine (1.27 mL, 7.32 mmol) followed by acetoxy methyl bromide/bromo methylacetate (0.896 g, 5.86 mmol) and the resulting reaction mixture was stirred overnight at ambient temperature. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent to afford the title compound as an oil (0.75 g, 72%). 1H NMR (300 MHz, CDCl3): 7.42(m, 2H), 6.97(dd, J=8.0 & 8.0 Hz, 1H), 5.73(s, 2H), 3.65(s, 2H), 2.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=O)[C:20](=[O:23])[C:19]=2[O:24]CC)=[CH:4][CH:3]=1.[NH2:27][C@@H:28]([CH2:30][CH3:31])[CH3:29].C(N(CC)CC)C>CC#N.CCO>[C@H:28]([NH:27][C:21]1[C:20](=[O:23])[C:19](=[O:24])[C:18]=1[NH:17][C:5]1[C:6]([OH:16])=[C:7]([S:8]([N:11]([CH2:12][CH3:13])[O:14][CH3:15])(=[O:10])=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:30][CH3:31])[CH3:29]
Reactant: CC[C@@H](C)N
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@@H](C)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Temperature: 70 °C

Procedure:
To a stirred solution of 6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Intermediate FA) (100 mg, 0.25 mmol) in MeCN (1 ml) and EtOH (1 ml) was added (R)-(−)-2-Aminobutane (30.7 mg, 0.42 mmol) followed by triethylamine (69 μl, 0.49 mmol). The reaction mixture was heated at 70° C. for 1 hour. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) and concentrated in vacuo. The residue was triturated with DCM to give a white solid; [M+H]+ 432.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (6H, m), 1.5-1.6 (2H, m), 3.3 (2H, m), 3.7 (3H, s, CH3) 4.1 (1H, m), 7.3 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][C:6]=2[N:7]=1.[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+]>COC1CCCC1.CCO.O.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH3:22])[C:5]4[CH2:10][N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][C:6]=4[N:7]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC(C)(C)C)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COC1CCCC1
Solvent: O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(CC(C)(C)C)C2
Yield: 18.4 %

Procedure:
(S)-4-(2-chloro-6-neopentyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 7) (assumed 0.56 mmol) was stirred in CPME:EtOH:Water (7:3:2, freshly mixed, 2 mL) with 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (203 mg, 0.67 mmol), Pd(PPh3)2Cl2 (20 mg, 0.028 mmol) and Na2CO3 (89 mg, 0.84 mmol) under a stream of nitrogen for 5 min, then irradiated in the microwave at 130° C. for 30 min. The reaction mixture was diluted with water and EtOAc and passed through a celite cartridge. The organic layer was concentrated in vacuo and purified by prep HPLC to give the desired compound as a yellow solid (48 mg, 0.103 mmol, 18% yield over three steps).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](O)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: OCC1CN(Cc2ccccc2)CCO1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a solution of 4-benzylmorpholine-2-carboxylic acid (5 g, 22.6 mmol) and triethylamine (3.35 mL, 24 mmol) in THF (100 mL) at −10° C. in a flask equipped with a condenser was added ethyl carbonochloridate (2.5 g, 23 mmol) dropwise and the mixture was stirred at −10° C. to −5° C. for 20 min. Sodium borohydride (2.27 g, 60 mmol) was added followed by methanol (25 mL) from the top of the condenser at such rate to maintain the temperature between 0-5° C. The reaction mixture was allowed to warm to room temperature, acidified to pH 5 with the addition of 10% aqueous citric acid, and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water, brine, and dried with MgSO4. Purification of the residue by column chromatography (SiO2, eluted with EtOAc) afforded 3 g of the title compound. MS (DCI/NH3) m/z 208 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[NH2:25][CH2:26][CH2:27][NH:28][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([C:10]2[NH:11][C:12](=[O:14])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:24])[CH:4]=3)[CH:9]=2)[CH:16]=1
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1cc(-c2cc(-c3cccc(C(=O)NCCN)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a solution of 3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid obtained from step 2 of Example 57 (16.9 mg, 48 μmol) and tert-butyl 2-aminoethylcarbamate (6.4 mg, 40 μmol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 μmol) followed by 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 μmol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo, taken up in methanol (1 mL) and 4.0 N hydrochloric acid in dioxane (1 mL), and stirred at room temperature for 4 hours then concentrated. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound N-(2-aminoethyl)-3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzamide (3.4 mg, 23%).
Reaction SMILES: [C:1](O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])([CH2:23][CH3:24])[CH3:22].S(=O)(=O)(O)O>C(O)(=O)C>[CH:21]([C:25]1[CH:30]=[C:29]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:28]=[CH:27][C:26]=1[OH:31])([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)c1ccccc1O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCC(C)c1cc(C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A 250 mL 1-neck flask was equipped with a magnetic stirrer and a reflux condenser with nitrogen blanket. The flask was charged with 6.52 grams (0.025 moles) of trityl alcohol, 3.77 grams (0.025 moles) of o-sec-butylphenol, and 50 mL of glacial acetic acid. The mixture was stirred under nitrogen at room temperature to give a clear, yellow solution. Concentrated sulfuric acid (5 mL) was then added in one portion. The solution immediately became dark red-brown. The solution was stirred at room temperature for 2 days, during which time solids separated out. The reaction mixture was filtered, and the solids were washed on the filter with several portions of water. After drying in a vacuum oven at 65° C. for 3 hours, the yield of product was 7.34 grams (75% yield). MP=135-136° C. GPC analysis showed a purity of >99%. The structure was confirmed by IR, 1H- and 13C-NMR analyses.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([NH2:11])=[O:10])=[N:5][N:4]=1)[CH3:2].Cl.N[C@@H:14]([CH2:17][CH2:18][N:19]1[CH2:22][CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=2)[CH2:20]1)[CH2:15][OH:16]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH:21]2[CH2:20][N:19]([CH2:18][CH2:17][C@H:14]([NH:11][C:9]([NH:8][C:6]3[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=3)=[O:10])[CH2:15][OH:16])[CH2:22]2)=[CH:25][C:26]=1[F:31]
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)c(F)c2)C1
Reactant: CCc1nnc(NC(N)=O)s1
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)c(F)c3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-chloro-3-fluoro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])CCC.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[N:18]=1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:21]1[CH:22]=[CH:17][N:18]=[C:19]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[N:20]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: Cn1ccc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 1-methyl-indole (244 mg, 1.86 mmol) in 10 ml of THF was treated with n-butyllithium (0.74 ml of a 2.5M solution in hexanes, 1.86 mmol) at −78° C. and the mixture was stirred under argon for 2 hours. In the meantime, a solution of (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (250 mg, 0.93 mmol) in 10 ml of THF was treated with n-butyllithium (0.74 ml of 2.5M solution in hexanes, 1.86 mmol) at −78° C. under argon for 15 minutes and the above solution containing the lithiated 1-methyl-indole was added with a syringe. The reaction mixture was stirred for 15 minutes at 0° C. and for 2 hours at room temperature. The reaction was quenched with saturated ammonium chloride solution (5 ml) and extracted with EtOAc. The organic layer was dried over sodium sulfate and evaporated. Purification by column chromatography on silicagel (EtOAc/MeOH/ammonia:2/1/0.02) gave the title compound. Yield: 92.5 mg (27%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[C:17]1[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])=[CH:19][CH:18]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:10]=[C:9]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:30])=[CH:19][CH:18]=3)[S:8][C:7]=12
Reactant: O=C1CCCN1CCc1ccc(Br)nc1
Reactant: Clc1ccnc2ccsc12
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCCN1CCc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To 7-chlorothienopyridine (0.95 g, 5.6 mmol) in THF (75 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 2.4 mL, 6.0 mmol), dropwise. The solution was stirred for 30 min then warmed to 0° C. and zinc chloride (1.0 M in ether, 6.5 mL, 6.5 mmol) was added. The reaction mixture was stirred for 20 min, then bromide 291 (1.25 g, 4.64 mmol) and tetrakis(triphenylphosphine) palladium (0.5.4 g, 0.46 mmol) in THF (15 mL) were added. The mixture then was heated to reflux for 3 h and cooled to RT. The excess base was quenched with 1 mL saturated aqueous ammonium chloride, and the mixture was concentrated. The residue was partitioned between water and diethyl ether, producing a yellow precipitate, which was isolated by suction filtration, triturated with ethyl acetate and dried in vacuo to give title compound 292 (1.2 g, 72%). MS (M+H): 358.3
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:5]1[CH2:4][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:2](=[O:1])[N:8]([CH2:9][C:10]([F:11])([F:12])[F:13])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CNCCN(CC(F)(F)F)C1=O
Reactant: O=Cc1cccc(F)c1F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A mixture of tert-butyl 7-oxo-1-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate (51 mg, 0.16 mmol), 2,3-difluorobenzaldehyde (0.053 mL, 0.49 mmol), and sodium cyanoborohydride (31 mg, 0.49 mmol) in methanol (5 mL) was adjusted to pH 4 with acetic acid. After 0.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (62 mg). MS 438 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23]OS(C)(=O)=O)[CH:20]=3)[NH:15][C:14]=2[CH3:29])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:20]=3)[NH:15][C:14]=2[CH3:29])=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OC(C)c1ccc(F)cc1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCCC3)cc2c1C(=O)OC(C)c1ccc(F)cc1
Yield: 79.7 %

Procedure:
To a solution of the product of Step A (58 mg, 0.14 mmol) in dioxane (1 mL) was added pyrrolidine (0.14 mL, 1.4 mmol) and the resultant solution was heated at 70° C. overnight. The reaction solution was concentrated in vacuo and the crude product purified by flash chromatography (9:1 Ethyl Acetate:Methanol w/0.5% triethylamine) to provide the compound (44 mg, 80%) as a yellow oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[NH:14][C:13](=[O:19])[CH2:12][CH2:11]2.CI.O>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]([CH3:1])[C:13](=[O:19])[CH2:12][CH2:11]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2cc(Br)c(Cl)cc2N1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(Br)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Potassium tert-butoxide (0.45 g, 4.0 mmol) was added at 0° C. to a solution of 6-bromo-7-chloro-3,4-dihydro-1H-quinolin-2-one (0.52 g, 2.0 mmol) in DMF (5 mL). Then, the reaction mixture was stirred at 0° C. for 30 min and methyl iodide (0.18 g, 1.29 mmol) was added. The resulting mixture was then stirred for 2 h before water was added. After extraction of the reaction mixture with EtOAc, the organic layer was washed with water and brine in sequence. Then, the organic layer was dried over anhy. Na2SO4 and the solvent was removed under reduced pressure to give a crude product (0.49 g, 90% yield) as a white solid. MS: 274.0 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5](Br)[C:6]2[N:7]([CH:9]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:11]=2)[CH:8]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)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>[Br:2][C:3]1[CH:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]2[N:7]([CH:9]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:11]=2)[CH:8]=1
Reactant: COC(=O)Cc1cn2cc(Br)cc(Br)c2n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)Cc1cn2cc(Br)cc(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 72.4 %

Procedure:
A solution of methyl 2-(6,8-dibromoimidazo[1,2-a]pyridin-2-yl)acetate hydrochloride (0.26 g, 0.68 mmol) and phenylboronic acid (0.083 g, 0.68 mmol) in toluene (9 mL) and ethanol (0.5 mL) was bubbled nitrogen for 20 mins. The mixture was then treated with Pd(PPh3)4 (26 mg, 0.022 mmol) and K3PO4 (2 M, 1 mL, 2.0 mmol) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (200 mL), washed with brine, separated, and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate in hexanes (10-25%) as eluent. The product containing fractions were concentrated to give 170 mg (73% yield) of methyl 2-(6-bromo-8-phenylimidazo[1,2-a]pyridin-2-yl)acetate as a white solid. LCMS B: 2.11 min (RT); (M+H)+=347.21 (100%), 345.21 (100%). 1H NMR, 400 MHz, CDCl3: δ 8.20 (d, J=1.6 Hz, 1 H), 7.96 (m, 2 H), 7.65 (s, 1H), 7.50-7.40 (m, 3 H), 7.33 (d, J=1.6 Hz, 1 H), 3.92 (s, 2 H), 3.75 (s, 3 H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)=[O:13])[CH2:8]2
Reactant: CN1CCNCC1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Solvent: CN1CCCC1=O
Product: CN1CCN(c2c(C(=O)NC3C4CC5CC(C4)CC3C5)cnn2C)CC1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A solution of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 59 mg; 0.20 mmol) and 1-methylpiperazine (0.47 mL; 4.2 mmol) in N-methylpyrrolidinone (0.8 mL) was heated to 230° C. in a sealed vial under microwave irradiation for 2 hr. The mixture was allowed to cool to room temperature and the crude product was purified by reverse phase HPLC to provide methyl-5-(4-methyl-piperazin-1-yl)-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (41 mg, 57%) as an off white solid. ES-HRMS m/e calcd for C20H32N5O (M+H+) 358.2602, found 358.2597.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:16]([C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:17]3[C:18](=[O:27])[NH:19][C:20]4[C:25]=3[C:24]=2[C:23]([F:26])=[CH:22][CH:21]=4)[CH2:9]1)=O)(C)(C)C.O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:26][C:23]1[C:24]2[C:25]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:27])[C:17]=3[C:16]([C:28]1[NH:29][CH:30]=[CH:31][CH:32]=1)=[CH:15][C:14]=2[S:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc(-c3ccc[nH]3)c3c4c(ccc(F)c24)NC3=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C1Nc2ccc(F)c3c(S[C@H]4CCNC4)cc(-c4ccc[nH]4)c1c23

Procedure:
(S)-3-[6-Fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (from Example 56 above) (54 mg, 0.12 mmol) was dissolved at 0° C. in a 50% TFA in CH2Cl2 solution (6 mL) that contained H2O (0.3 mL). After 2 hours the reaction mixture was partitioned between ethyl acetate and aqueous 1 N NaOH. The pH of the aqueous layer was adjusted to 14. The aqueous layer was extracted twice with ethyl acetate and the combined organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by a precipitation out of THF with excess of pentane to give 6-fluoro-5-[(S)-(pyrrolidin-3-ylsulfanyl)]-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 41 mg; 97%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1)([CH3:14])[CH3:13]
Reactant: CC(C)N
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1nc(NC(C)C)ccc1[N+](=O)[O-]

Procedure:
6-Chloro-2-methyl-3-nitro-pyridine (0.5 g) was treated with isopropyl amine according to General Procedure U to give isopropyl-(6-methyl-5-nitro-pyridin-2-yl)-amine LCMS (m/z): 196. This was reduced under hydrogen atmosphere according to General Procedure Z to give N*2*-Isopropyl-6-methyl-pyridine-2,5-diamine (0.35 g), LCMS (m/z): 166. This was converted to 6-isopropylamino-2-methyl-pyridine-3-sulfonyl chloride according to General Procedure AA.