Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[N+:22]([O-])=O)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:22][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]#[CH:21])=[CH:17][C:12]=1[C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)=[O:11]
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 10.59 g (30.7 mmol) (4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanone in 250 ml acetic acid are added 13.6 g (246 mmol) iron powder. After stirring for 20 h at rt the reaction mixture is basified by the addition of 2M sodium hydroxide solution, filtered and extracted with dichloromethane. Aider purification by chromatography using hexanes/ethyl acetate (7:3) as eluent (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[OH:9])[CH:5]=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][CH2:21][CH2:20]2.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.[Cu]I>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=3)=[O:9])[CH:3]=1)[CH2:21][CH2:20]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: Cn1ccnc1C(O)c1cncc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ccnc1C(=O)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 150 °C
Yield: 2.5 %

Procedure:
(5-Bromo-pyridin-3-yl)-(1-methyl-1H-imidazol-2-yl)-methanol (150 mg, 0.56 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (90 mg, 0.49 mmol) (intermediate A-2), CuI (30 mg, 0.16 mmol), Cs2CO3 (330 mg, 1.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.08 mL, 0.64 mmol) were dissolved in dioxane (4.0 mL). The resulting mixture was heated at 150° C. for 2 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×75 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give the title compound (4.5 mg, 2.5%) as light yellow oil. MS: 367.1 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:10][C@H:11]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[NH:1]([C:2]([NH:10][C@H:11]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using isocyanatobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 499.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[O:17][C:18]([CH3:24])=[C:19]([C:21](Cl)=[O:22])[N:20]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:19]1[N:20]=[C:16]([CH3:15])[O:17][C:18]=1[CH3:24])=[O:22]
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c(C)o1
Yield: 66.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0459 g, 0.195 mmol), 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (0.032 g; 0.195 mmol), and triethylamine (0.0683 mL; 0.486 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.0414 g (67%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-2,5-dimethyloxazole-4-carboxamide as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Temperature: 50 °C
Reaction time: 144 h
Yield: 54.9 %

Procedure:
A mixture of 2-amino-5-morpholin-4-yl-benzamide (820.0 mg, 3.71 mmol, Heterocyclic Comm. 2001, 7, 473-480), 2,4,5-trichloropyrimidine (679.8 mg, 3.71 mmol) and potassium carbonate (614.6 mg, 4.45 mol) in THF (10 mL) was stirred at 50° C. for 20 h and at RT for 6 days. The reaction was diluted with water (10 mL) and extracted into EtOAc. The organic layer was washed with NaHCO3, brine and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue triturated with ether (5×3 mL) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-benzamide as a yellow solid (0.75 g) that was used without further purification in the subsequent step.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:14]([C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH:15]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CC(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C

Procedure:
A solution of 48 g (0.30 mole) of 3-diazooxindole and 38.7 g (0.39 mol) of ethyl propiolate in 2 l. of benzene is refluxed overnight. The reaction mixture is cooled to room temperature and the crude product filtered, wt.=60 g. Crystallization from absolute ethanol gives 54 g, m.p. 242°-244° (Sl. d.).
Reaction SMILES: CO.C1COCC1.C[O:9][C:10](=[O:39])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29](=[N:36][O:37][CH3:38])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH3:38][O:37]/[N:36]=[C:29](/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)\[CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:10]([OH:39])=[O:9])=[CH:14][CH:15]=2)=[CH:22][CH:23]=1
Reactant: CON=C(COc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 2 mL of methanol and 1 mL of THF. To the stirred solvent, was added 3-{4-[4-(2-methoxyimino-2-phenyl-ethoxy)-benzyloxy]-phenyl}-propanoic acid methyl ester (0.085 g, 0.19 mmol). To the stirred solution, NaOH (0.015 g, 0.375 mmol) in water (1 mL) was added. The resulting solution was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was evaporated under reduced pressure. The RM was diluted with 1 mL of water, cooled to 0° C., then acidified with 1N HCl (5 mL), and extracted with ethyl acetate (10 mL×2), organic layer was given water (5 mL) and saturated brine solution wash (5 mL), dried over anhydrous Na2SO4 and evaporated to dryness to yield colorless solid (0.050 g, yield: 63.3%); purity: 97.65%.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([CH3:5])[C:3]#[N:4].[OH-:15].[K+].OO>CC(O)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([CH3:1])[C:3]([NH2:4])=[O:15]
Reactant: [OH-]
Reactant: CC(C)(C#N)c1cccc([N+](=O)[O-])c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: OO
Agent: [Cl-]
Solvent: CC(C)O
Product: CC(C)(C(N)=O)c1cccc([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-methyl-2-(3-nitrophenyl)propanenitrile (1.5 g, 7.89 mmol) in 2-propanol was added benzyltriethyl ammonium chloride (0.054 g, 0.237 mmol) and 25% aq. KOH solution (5.0 ml). Resulting solution was stirred for 5 min. and H2O2 (2.5 ml, 30% aq. solution) was added (slow addition). Reaction mixture was heated at 75° C. for 4 hr. Solvent was evaporated under vacuum and residue was suspended in water (200 ml). Precipitate was filtered and dried to obtain 2-methyl-2-(3-nitrophenyl)propanamide (0.98 gm).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[C:26]([O:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34](O)=[O:35])(=[O:28])[CH3:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:26]([O:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:35])(=[O:28])[CH3:27]
Reactant: CC(=O)Oc1ccccc1C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccccc1OC(C)=O
Yield: 83.1 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (3.0 g), triethylamine (1.7 mL), 2-acetoxycinnamic acid (2.5 g), WSC.HCl (2.4 g), and methylene chloride (80 mL), to give the captioned compound (3.9 g, 83%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>CCCCCC.CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2cc(N)cc(C(F)(F)F)c2)cc1

Procedure:
The title compound is prepared as described in Example 13 but using 3-amino-5-bromobenzotrifluoride (RYAN SCIENTIFIC) and 4-methoxyphenylboronic acid (Aldrich). Title compound: ES-MS: 266.0 [M-H]−; single peak at tR=4.61 min (System 1); Rf=0.20 (Hexane/EtOAc, 3:1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:9]2(=[O:25])=[O:24])=[CH:5][CH:4]=1.[CH3:28][NH2:29]>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([CH2:7][C:6]2[CH:26]=[CH:27][C:3]([CH2:2][NH:29][CH3:28])=[CH:4][CH:5]=2)[S:9]1(=[O:24])=[O:25]
Reactant: CN
Reactant: O=S1(=O)N(Cc2ccc(CBr)cc2)c2ccccc2N1c1ccccc1F
Product: CNCc1ccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)cc1
Yield: 100 %

Procedure:
In an analogous manner to general procedure V, 1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.11 g, 0.24 mmol) was treated with methylamine (10 mL) to provide 0.09 g, (100%) of 1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine. MS (ES) m/z 397.0. HPLC purity 100.0% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:24])[C:11]([OH:23])=[CH:12][C:13]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].C([O:27][C:28](=[O:32])[CH:29](Cl)Cl)C.Cl>COCCOC.O>[CH3:7][C:8]1[C:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:12][C:11]2[O:23][CH:29]([C:28]([OH:32])=[O:27])[O:24][C:10]=2[CH:9]=1
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2c(cc1S(=O)(=O)c1ccccc1)OC(C(=O)O)O2

Procedure:
27.7 g (200 mmol) of anhydrous potassium carbonate are added to a suspension of 10.6 g (40 mmol) of 4-methyl-5-phenylsulphonyl-1,2-benzenediol in 65 ml of cold 1,2-dimethoxyethane. While stirring vigorously, a solution of 7.85 g (50 mmol) of dichloroacetic acid ethyl ester in 5 ml of 1,2-dimethoxyethane is added dropwise thereto in the course of 30 minutes. The mixture is stirred for a further hour at room temperature and is then boiled under reflux for 3 hours while stirring. It is then cooled to 30°, water is added, and the whole is stirred for 30 minutes and adjusted to pH 1-2 with hydrochloric acid. Some of the 1,2-dimethoxyethane is removed in a rotary evaporator and the solution remaining is extracted three times with ethyl acetate. The combined ethyl acetate solutions are washed with water, and then with saturated sodium chloride solution, dried over sodium sulphate, treated with activated carbon and concentrated by evaporation. The resulting yellow-green oil is crystallised from ethyl acetate/hexane. The sand-coloured crystals are dissolved in ethyl acetate and treated again with activated carbon. The solvent is removed in a rotary evaporator. The yellow oil remaining is crystallised from methylene chloride at 0°, yielding 5-methyl-6-phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid having a melting point of 169°-171°.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:22][CH2:21][C:16]3([O:17][CH2:18][CH2:19][O:20]3)[CH2:15][CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:31]1[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=[C:30]1[CH3:29])=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cn1c(CN2CCC3(CC2)OCCO3)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)OCCO4)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 8-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-1,4-dioxa-8-azaspiro[4.5]decane and 2-methybenzimidazole were reacted to give 369. LCMS m/z: 505.2 (MH+)
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([C:8]([N:10]2[C@@H:14]3[CH2:15][CH2:16][C@H:11]2[C@H:12]([NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH2:13]3)=[O:9])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][CH:36]=[CH:37][N:38]=1)CCC>COCCOC.[Cu]I.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>[F:1][C:2]1[C:3]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[C:4]([C:8]([N:10]2[C@@H:14]3[CH2:15][CH2:16][C@H:11]2[C@H:12]([NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH2:13]3)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: O=C(c1cccc(F)c1I)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(c1cccc(F)c1-c1ncco1)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Temperature: 145 °C
Yield: 70.8 %

Procedure:
In a microwave vial was dissolved the title compound of Example 277 (30 mg, 0.06 mmol) and 2-(tributylstannyl)oxazole (15 μL, 0.07 mmol) in DME (1 mL). The solution was degassed with N2 for 5 minutes then CuI (1 mg, 0.0045 mmol) and Pd(PPh3)4 (5 mg, 0.0045 mmol) were added. The reaction was purged with N2 and heated at 145° C. for 3 h. The reaction was cooled to rt, filtered through a pad of celite and purified via prep HPLC to give the title compound (19 mg, 72%). MS (ESI) mass calcd. for: C21H17F4N5O2, 447.1; m/z found 448.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) 8.49 (s, 1H), 8.36 (s, 0.8H), 7.85 (s, 0.8H), 7.76 (s, 0.4H), 7.62-7.45 (m, 1H), 7.43-7.33 (m, 1H), 7.32-7.23 (m, 2H), 7.23-7.09 (m, 1H), 4.91-4.85 (m, 0.4H), 4.78 (d, J=5.4 Hz, 0.6H), 4.42 (td, J=8.6, 2.8 Hz, 0.6H), 4.28 (td, J=8.2, 3.6 Hz, 0.4H), 4.00-3.95 (m, 0.6H), 3.89 (d, J=4.4 Hz, 0.4H), 2.23-1.44 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH2:15]I)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]1[CH:31]=[C:30](I)[CH:29]=[C:28]([F:33])[C:27]=1[N:34]1[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36](=[O:50])[CH2:35]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:30]1[CH:29]=[C:28]([F:33])[C:27]([N:34]2[CH2:35][C:36](=[O:50])[N:37]([CH2:41][O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[S:38]2(=[O:40])=[O:39])=[C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:31]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CN(c2c(F)cc(I)cc2OCc2ccccc2)S(=O)(=O)N1COCc1ccccc1
Reactant: Cc1ccc(CI)c(NC(=O)OC(C)(C)C)c1
Product: Cc1ccc(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound is prepared analogously to Example 1, Step M, with (2-iodomethyl-5-methylphenyl)-carbamic acid tert-butyl ester and 5-(2-benzyloxy-6-fluoro-4-iodophenyl)-2-benzyloxymethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:24]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19]([NH2:24])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(Br)cc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(Br)cc1

Procedure:
In an analogous manner to that described in Example 4, from 3-(4-bromo-benzenesulphonyl)-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-bromo-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [F:1][C:2]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:3]=1[O:4][C:5]1[C:10]2[NH:11][C:12](=[O:14])[NH:13][C:9]=2[C:8]([CH:15]=O)=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1.[NH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N.[Na+]>CO.C(Cl)Cl.C(#N)C.O>[F:1][C:2]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:3]=1[O:4][C:5]1[C:10]2[NH:11][C:12](=[O:14])[NH:13][C:9]=2[C:8]([CH2:15][NH:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(C=O)c5[nH]c(=O)[nH]c5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Reactant: NCCN1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(CNCCN5CCOCC5)c5[nH]c(=O)[nH]c5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
A suspension of 7-(2,4-difluorophenoxy)-6-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-oxo-2,3-dihydro-1H-benzimidazole-4-carbaldehyde (25.0 mg, 0.0423 mmol) and N-(2-aminoethyl)morpholine (0.0111 mL, 0.0847 mmol) in methanol (0.40 mL) and methylene chloride (0.40 mL) was heated to 60° C. and stirred at 60° C. for 1 h. The reaction mixture was cooled to 0° C., treated with sodium cyanoborohydride (0.0106 g, 0.169 mmol), warmed to RT and stirred for at RT 15 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in methanol (0.50 mL), treated with sodium cyanoborohydride (0.00532 g, 0.0847 mmol), and stirred at 60° C. for 3 h. The reaction mixture was diluted with acetonitrile, methanol and a few drops of water and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (11.9 mg, 40%). LCMS calculated for C35H35F2N6O6S (M+H)+: m/z=705.2. found: 705.2.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Yield: 0.1 %

Procedure:
Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 7 mg, 0.016 mol) in pyridine (1 ml) was reacted with acetyl chloride (1.0 μl, 0. 16 mmol) to yield the title compound (8 mg, 100%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C(OC)(OC)OC.CC(O)=O.[O:52]1[CH2:55][C:54](=O)[CH2:53]1.[BH3-]C#N.[Na+]>CO.CCOC(C)=O.C1COCC1>[Si:34]([O:33][C@H:3]1[C@H:2]([NH:1][CH:54]2[CH2:55][O:52][CH2:53]2)[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:25][CH2:26]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1NC1COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
(+/−)2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171C)(60 mg, 0.104 mmol) was taken up in MeOH (1 mL) and THF (1 mL) and trimethyl orthoformate (0.859 mL, 7.77 mmol), AcOH (0.024 mL, 0.414 mmol), and oxetan-3-one (0.066 mL, 1.036 mmol) were added. The reaction was stirred at room temperature for 2 h, then NaCNBH3 (65.1 mg, 1.036 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography, eluting with 0-3% MeOH/DCM. (+/−)-2-((3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(oxetan-3-ylamino)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg) was obtained as a white foam.