Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CN1CCOCC1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1c(NS(C)(=O)=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a slurry of 6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (Example 11B) (14 mg, 0.035 mmol) in CH2Cl2 (2 ml) was added N-methyl morpholine (12.3 μl, 0.113 mmol) followed by MsCl (4.5 μl, 0.057 mmol). The reaction mixture was stirred overnight, 10% citric acid (3 ml) was added. The resulting mixture was extracted with CHCl3 (10 ml), the organic layer was separated and dried with Na2SO4, concentrated to give the title compound (6.9 mg, 45%). It has a retention time of 6.01 min (standard LCl method, 8 min run). MS Found: (M+H)+=434.0
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c1nc(N)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
To a solution of 0.1 g (0.52 mmol) of 2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester (intermediate A) in DMSO (1 mL) was added 0.089 g (0.52 mmol) of benzyl bromide, the reaction mixture was stirred at room temperature for 3 h. The conversion was monitored by LCMS. After usual work up, the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1) to afford 0.08 g (55%) of 2-amino-1-benzyl-1H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 281 (M+1)+; 1H NMR (DMSO-d6, 400 MHz): δ 7.49 (dd, 1H), 7.29 (t, 2H), 7.25 (m, 2H), 7.16 (m, 2H), 7.05 (bs, 2H), 6.85 (t, 1H), 5.28 (s, 2H), 3.79 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:11][C:10]=2[O:26][CH3:27])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:26][CH3:27])=[CH:11][C:12]([N:18]3[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 93.6 %

Procedure:
A mixture of 5-chloro-N-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 62, 295 mg, 0.58 mmol), iron (194 mg, 3.48 mmol) and NH4Cl (23 mg, 0.43 mmol) were heated at reflux in ethanol (12 mL) and water (4 mL) for 1.5 h. The mixture was then cooled and concentrated in vacuo. The residue was triturated in 10% CH3OH in CH2Cl2 (25 mL) for 15 minutes and then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (25 mL) and filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (260 mg, 94%) as a yellow gum; 1H NMR: 1.73-1.86 (1H, m), 2.01-2.12 (1H, m), 2.20 (6H, s), 2.81-2.91 (1H, m), 2.92-3.05 (2H, m), 3.16 (1H, dd), 3.2-3.27 (1H, m), 3.67 (3H, s), 4.25 (2H, d), 6.71 (1H, s), 6.93 (1H, s), 7.12 (1H, td), 7.3-7.37 (1H, m), 8.36 (1H, s), 8.38-8.46 (2H, m), 8.82 (1H, dt), 8.94 (1H, s); m/z: ES+ MH+ 479.5.
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12].[F:31][C:32]([F:49])([F:48])[C:33]1[CH:47]=[CH:46][C:36]([CH2:37][O:38][C:39](N2C=CN=C2)=[O:40])=[CH:35][CH:34]=1>C(OCC)(=O)C>[F:31][C:32]([F:48])([F:49])[C:33]1[CH:47]=[CH:46][C:36]([CH2:37][O:38][C:39]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([C:21]3[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([O:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:30])[CH:22]=3)[CH2:24]2)=[O:40])=[CH:35][CH:34]=1
Reactant: CCOC(=O)COc1cc(C2CCCNC2)ccc1C
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
(2-methyl-5-piperidin-3-yl-phenoxy)-acetic acid ethyl ester L-tartaric acid salt (Example 12; 147 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 3 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (93 mg, 0.34 mmol) was added. The reaction was stirred for 18 h at room temperature under nitrogen. The reaction was flash chromatographed with 15% ethyl acetate/hexanes to yield 118 mg (74%) of the desired 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O-])(=O)C.[K+].[CH:23]1([OH:28])[CH2:27][CH2:26][CH:25]=[CH:24]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:1]([C@@H:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([CH:25]3[CH2:26][CH2:27][C:23](=[O:28])[CH2:24]3)[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OC1C=CCC1
Reactant: CCCCCC[C@@H]1CCc2cc(I)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCC[C@@H]1CCc2cc(C3CCC(=O)C3)ccc2C1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
Nitrogen gas was bubbled through a mixture of (R)-2-hexyl-6-iodo-1,2,3,4-tetrahydronaphthalene (I-8D, 11.8 g, 34.5 mmol), tetrabutylammonium chloride (9.58 g, 34.5 mmol), potassium acetate (10.15 g, 103 mmol), palladium (II) acetate (0.774 g, 3.45 mmol), and anhydrous DMF (100 mL) for 3 min before cyclopent-2-enol (6.8 g, 81 mmol, prepared according to Larock, R. C. et al., Tetrahedron, 50(2):305-321 (1994)) was added. Nitrogen gas was bubbled through the solution for an additional 2 min. The mixture was stirred at 80° C. under nitrogen for 2.5 h and then concentrated to remove DMF. The residue was mixed with water (150 ml) and extracted with ethyl acetate (4×50 mL). The combined ethyl acetate solutions were washed with water (30 mL), dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure. Flash chromatography purification (220 g silica gel column, gradient elution from 5 to 50% ethyl acetate in hexanes) afforded 3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanone (5.96 g, 19.97 mmol) LC/MS M+1=299.
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:7])[CH3:6].C(O[C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)[CH:17]=1)=O)C>C1COCC1>[Br:24][C:20]1[CH:19]=[C:18]([N:16]2[CH:17]=[C:13]([C:11]3[O:3][N:4]=[C:5]([CH3:6])[N:7]=3)[N:14]=[CH:15]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)cn1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cn(-c3cccc(Br)c3)cn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a suspension of NaH (1.30 g, 32.64 mmol, 60% in mineral oil) in THF (15 mL) under nitrogen atmosphere was added N-hydroxy-acetamidine (2.62 g, 35.4 mmol) and stirred for 1 h at room temperature. The bromo ester 3 (8 g, 27.2 mmol) in THF (2 mL) was added and refluxed for 12 h. The reaction mixture was quenched by adding brine, extracted with ethylacetate (100 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography using 25% ethylacetate in hexane as mobile phase to furnish 4 (2.8 g, 35%) as pale yellow solid, mp=200.1-202.4° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]([CH2:10][O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:9])=O)C.[NH3:28]>C(O)C>[NH2:28][C:4](=[O:3])[CH2:6][NH:7][C:8]([CH2:10][O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:9]
Reactant: N
Reactant: CCOC(=O)CNC(=O)COC[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCO
Product: NC(=O)CNC(=O)COC[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 120 h

Procedure:
(S)-Phenylmethyl 2-[[[[[(ethoxycarbonyl)methyl]amino]carbonyl]methoxy]methyl]-1-pyrrolidinecarboxylate, 4 g (0.01057 mol), is dissolved in 100 ml of ethanol and the solution saturated with ammonia at room temperature. The solution is allowed to stand at room temperature for five days, the solvent evaporated in vacuo and the residue dissolved in 100 ml of methanol and the solution saturated with ammonia at room temperature. The solution is allowed to stand at room temperature for 14 hours and the solvent evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (90:10) to give (S)-phenylmethyl 2-[[[[(2-amino-2-oxoethyl)amino]carbonyl]methoxy]methyl]-1-pyrrolidinecarboxylate, 3 g; mp 109.5°-111°; [α]D25 -41.0° (c 0.57, methanol).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:14]Br>CN(C=O)C>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrCBr
Reactant: CC(=O)Oc1ccc(C=O)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OC(C)=O)cc1
Reaction time: 1 h

Procedure:
Then a mixture obtained by mixing 32.8 g of p-acetoxybenzaldehyde (PABA) (0.2 mol) and 52.15 g of dibromomethane (0.3 mol) in 85 g of anhydrous DMF was dropping for 1 hour keeping the internal temperature at 50° C. Then agitation was continued for 40 minutes under the same temperature.
Reaction SMILES: [CH2:1](B1C2CCCC1CCC2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: Nc1ccc(I)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Nc1ccc(Cc2ccccc2)cn1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
9-Benzyl-9-bora-bicyclo[3.3.1]nonane (0.5M solution in THF, 12727 μL, 6363 μmol) was added to a mixture of 5-iodopyridin-2-amine (700 mg, 3182 μmol), potassium phosphate (2026 mg, 9545 μmol), Pd2 dba3 (58 mg, 64 μmol), and X-Phos (61 mg, 127 μmol) suspended in H2O (1 mL) in a sealable reaction vial. The vial was flushed with argon gas and then sealed and heated (microwave) at 120° C. for 30 min. The crude mixture was diluted with EtOAc, and the resulting solution was sequentially washed with 1M NaOH and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was taken up in MeOH (5 mL), concentrated aqueous HCl (0.30 mL) was added, and the resulting solution was stirred 10 min. Solid NaOH (120 mg) was then added, and the resulting solution was concentrated onto silica gel. Chromatographic purification of the product (ISCO, 12 g, 0-10% MeOH/CH2Cl2) furnished 5-benzylpyridin-2-amine as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.95 (s, 1H), 7.28 (t, J=7.5 Hz, 2H), 7.23 (d, J=11.0 Hz, 2H), 7.17 (t, J=8.5 Hz, 2H), 6.44 (d, J=8.5 Hz, 1H), 4.34 (s, 2H), 3.80-3.86 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH2:16][C:17]#[N:18])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>[Ni].C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH2:16][CH2:17][NH2:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2CC#N
Agent: [Ni]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2CCN

Procedure:
The compound prepared in (2) above (650 mg) was dissolved into a mixed solvent of 10 ml of acetic acid and 30 ml of acetic anhydride. The mixture was catalytically hydrogenated with the addition of 2 ml of Raney nickel. After removing the catalyst by filtration, the reaction mixture was concentrated and chloroform was added to the residue, which was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was recrystallized from chloroform and ether to obtain 510 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([F:21])=[CH:13][CH:12]=2)[CH:8]=[C:7]([CH:22]([CH3:24])[CH3:23])[N:6]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CCOCC>[CH3:25][S:26]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([F:21])=[CH:13][CH:12]=2)[CH:8]=[C:7]([CH:22]([CH3:24])[CH3:23])[N:6]=1)(=[O:28])=[O:27]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(NCCN)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(NCCNS(C)(=O)=O)n1

Procedure:
To a solution of 2-(2-aminoethyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.170 g) dissolved diethyl ether was added dropwise a solution of methansulfonyl chloride (0.060 g) in ether. The reaction was carried out at room temperature, and after 1 hour the solvent was removed under reduced pressure. The crude material was taken up in methylene chloride and the free base was liberated by the addition of sodium carbonate solution. The organic layer was dried over magnesium sulfate and the reaction product isolated by evaporation, purified by column chromatography on silica gel, eluting with ethyl acetate/hexane to give 2-(2-methanesulfonamidoethyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine. The hydrochloride salt of the product was made (0.180 g), m.p. 85-91° C. (C 54.67%, H 5.59%, N 12.48%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Product: COc1ccc(-c2ccc([C@H]3CCC[C@H]3NS(=O)(=O)C(C)C)cc2)cc1
Yield: 89.2 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (200 mg, 0.51 mmol, prepared in example 17) and 4-methoxyphenylboronic acid (93 mg, 0.61 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride to afford 170 mg (89%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15](OC)=[O:16])=[CH:11][C:10]=2[C:19]2[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH:20]=2)[CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[F:27][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[C:19]2[C:23]([CH3:24])([CH3:25])[CH2:22][CH2:21][CH:20]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)F)ccc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 77 %

Procedure:
To a cooled solution of T34.2 (0.2349 g, 0.6274 mmol) in dry THF (5 mL) at 0° C. was added LAH (1.0 M in THF)(1.3 mL, 1.3 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and was monitored by TLC and LCMS. After 45 minutes, 1N NaOH was added to quench the reaction (gas evolution occurred). The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-50% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to a colorless oil as T34.3 (166.6 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (2H, m), 7.38 (2H, m), 7.14 (1H, t, J=9.0 Hz), 6.62 (1H, t), 5.50 (1H, td, J=2.4, 1.0 Hz), 4.76 (2H, s), 2.23 (2H, td, J=7.0, 2.3 Hz), 1.74 (3H, m), 0.85 (6H, s).
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:7]=1.BrB(Br)Br.CC(=CC)C.C([O-])(O)=O.[Na+]>O.ClCCl>[CH3:18][C:16]1[N:17]=[C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[OH:2])[CH:11]=[CH:10][N:9]=2)[S:14][CH:15]=1
Reactant: COc1ccccc1Oc1ccnc(Nc2nc(C)cs2)c1
Agent: BrB(Br)Br
Agent: CC=C(C)C
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: Cc1csc(Nc2cc(Oc3ccccc3O)ccn2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A 50 mL round bottom flask was charged with 4-(2-methoxyphenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (6.38 mL, 0.638 mmol) and dichloromethane (6 mL). The solution was cooled to 0° C., and tribromoborane (0.181 mL, 1.91 mmol) and 1 mL of 2-methyl-2-butene were added. The reaction mixture was stirred at 0° C. for 1 hour. Water and saturated solution of NaHCO3 were added, and the reaction mixture was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified on a prepacked silica gel column, eluting with 20-35% EtOAc in hexanes to give 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenol (0.130 g, 67.4% yield) as light yellow solid. 1H NMR (DMSO) δ 10.90 (bs, 1H), 9.70 (bs, 1H), 8.10 (d, 1H), 7.11 (m, 2H), 7.01 (dd, 1H), 6.87 (dt, 1H), 6.49 (d, 1H), 6.43 (m, 2H), 2.19 (d, 3H); Mass spectrum (esi) m/z=300 (100) (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]2[NH:33][C:32](=[O:34])[N:31]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:30][CH2:29][C:28]=2[CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([C:10]([C:4]1[N:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([N:38]3[CH2:37][CH2:36][CH:35]([N:31]4[CH2:30][CH2:29][C:28]5[CH:41]=[C:24]([O:23][CH3:22])[CH:25]=[CH:26][C:27]=5[NH:33][C:32]4=[O:34])[CH2:40][CH2:39]3)[CH:3]=1)=[O:11])[CH2:13][CH2:14]2
Reactant: N#Cc1cnc(C(=O)N2CCc3cc(F)ccc32)cc1Cl
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3C#N)CC1)C(=O)N2

Procedure:
150 mg (0.50 mmol) 4-chloro-6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-nicotinonitrile, 137 mg (0.50 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 103 mg (0.75 mmol) potassium carbonate in 2 mL DMF were stirred for 10 h at 130° C. Then the reaction mixture was diluted with 4 mL DMF and the precipitate formed was suction filtered. The filtrate was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[N:31]=[C:30]([CH2:32][OH:33])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:15]1([NH:14][C:12](=[O:13])[C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([CH2:32][OH:33])[N:31]=4)=[CH:23][CH:22]=3)[CH:10]=2)[CH2:16][CH2:17]1
Reactant: OCc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CO)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (100 mg, 0.323 mmol), [6-(bromomethyl)pyridin-2-yl]methanol (71 mg, 0.355 mmol) and potassium carbonate (49 mg, 0.355 mmol) were mixed in acetonitrile (3 mL) and the reaction was stirred at room temperature for 16 h. The reaction was then heated at 100° C. in the microwave for 10 mins. Water (10 mL) was added and the mixture was extracted with DCM (3×15 mL). The organic layers were combined and evaporated to give a white solid which was triturated with DCM to give the title compound as a white solid (80 mg, 58%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 4.59 (s, 2H), 5.24 (s, 2H), 7.16 (d, 2H), 7.32 (d, 1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97 (d, 2H), 8.36 (d, 1H), 9.82 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:16])C>Cl>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:17])=[O:3])[C:7](=[O:16])[CH2:8]2
Reactant: CCOC(=O)CN1C(=O)Cc2cc(Cl)ccc21
Agent: Cl
Product: O=C(O)CN1C(=O)Cc2cc(Cl)ccc21
Temperature: 80 °C
Yield: 84.1 %

Procedure:
In a two neck flask, ethyl (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate 58 (0.1 g, 0.39 mmol) was stirred overnight at room temperature in aqueous HCl (6 M, 2 ml) and warmed at 80° C. until disappearance of the starting material by TLC. The reaction mixture was cooled down to room temperature, filtered and the filtrate was washed by cold water to afford (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid 59 (74 mg).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[CH:26]=[CH:27][CH2:28][OH:29])=O)C1C=CC=CC=1>CO>[NH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][OH:29]
Reactant: O=C(OCc1ccccc1)N1CCCC1Cc1c(C=CCO)oc2ccccc12
Solvent: CO
Product: OCCCc1oc2ccccc2c1CC1CCCN1
Reaction time: 2 h

Procedure:
A mixture of 60 (1.1 g, 2.8 mmol) and 10% Pd-on-carbon (1 g) in MeOH (40 mL) was placed under an atmosphere of hydrogen gas (45 PSI) and shaken for 2 h using a Parr apparatus. The catalyst was removed by filtration through a bed of celite and the clarified filtrate was concentrated in vacuo to afford 725 mg (quant.) of 61 as a yellow oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.47-7.36 (m, 2H), 7.21-7.17 (m, 2H), 4.59 (br s, 2H), 3.57-3.50 (m, 2H), 3.40-3.31 (m, 1H), 3.08-2.94 (m, 1H), 2.89-2.69 (m, 2H), 2.05-1.95 (m, 2H), 1.93-1.49 (m, 2H) ppm.