Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@:3]1([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12])[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[H][H]>CCOC(C)=O.[Pd]>[OH:1][CH2:2][C@@:3]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12])[O:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: CCCCCCCCCCCCCCOC(=O)C=C[C@]1(CO)CCC(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)CC[C@@]1(CO)CCC(=O)O1
Yield: 98.2 %

Procedure:
A solution of 3.5 (0.154 g, 0.4 mmol) in EtOAc (20 mL) was treated with 10% Pd-C (0.4 g) and hydrogenated under a hydrogen balloon for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography over silica gel with EtOAc:hexanes (2:1) as eluant to give 3.3 (0.151 g, 98%) as a white solid; mp 59° C.; [α]22D +7.90° (c 1.0, CHCl3). The IR, 1H NMR, and 13C NMR were identical to those reported for the racemate 3.2. Anal. Calcd for C22H40O5 : C, 68.71; H, 10.48. Found: C, 68.81; H, 10.45.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH2:29][O:30]C3CCCCO3)[CH:20]=2)[CH2:15][CH2:14]1.Cl>CO>[OH:30][CH2:29][CH2:28][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:37])=[O:2])[CH2:18][CH2:17]2)=[CH:20]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2cn(CCOC3CCCCO3)c3ccccc23)CC1
Agent: Cl
Solvent: CO
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCO)c3ccccc23)CC1

Procedure:
To a solution of 0.7 g (1.4 mmol) of 2-[2-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-benzoic acid methyl ester in 10 mL of methyl alcohol, 10 mL of a solution of methyl alcohol saturated with hydrogen chloride were added. The crude mixture was heated at 70° C. for 1 hour and the solvent was removed under reduced pressure. After addition of 20 mL of water, the crude mixture was neutralised with 2N NaOH and the aqueous phase was extracted with chloroform. After removal of the solvent at reduced pressure 0.5 g of the desired product were obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[N:27]=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=1)=[O:11].[OH-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:27]=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([OH:21])=[O:20])=[CH:28][CH:29]=1)=[O:11]
Reactant: CCOC(=O)c1cccnc1Oc1ccc(C(=O)c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(Oc2ncccc2C(=O)O)cc1)c1nc2ccccc2[nH]1

Procedure:
To the solution of ethyl 2-(4-(1H-benzo[d]imidazole-2-carbonyl)Phenoxy)nicotinate (12.0 g, 30.9 mmol) in methanol (100 mL) was added aqueous solution of NaOH (1.85 g, 46.3 mmol, 30 mL). The reaction mixture was heated up to reflux for 1 h. The reaction mixture was concentrated, diluted with water and filtered. The aqueous layer was washed with ethyl acetate and acidified by addition of 2N HCl to pH 6. The brown precipitate was collected by filtration, dried to give the title compound. MS (ESI, pos. ion) m/z: 360.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.[CH:28]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[CH:28]1([CH2:31][C:32]([NH:1][CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]3[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH2:8][CH2:9]2)=[O:33])[CH2:30][CH2:29]1
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC1CC1)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: -20 °C

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (70 mg, 0.18 mmol), TEA (123 μL, 0.881 mmol), and 2-cyclopropylacetic acid (35 mg, 0.35 mmol) in a 1:1 mixture of CH2Cl2:DMF (2 mL) was treated with a solution of HATU (100 mg, 0.264 mmol) in DMF (1 mL). The reaction was stirred over night then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously and allowed to separate for 15 min. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:7](C)[C:6](C2C=CN=CC=2)=[N:5][N:4]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=1)[C:19](Cl)=O>>[F:15][C:16]1[CH:17]=[C:18]([C:19]2[N:2]([CH3:1])[C:3]([NH:7][CH3:6])=[N:4][N:5]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CNc1nnc(-c2ccncc2)n1C
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: CNc1nnc(-c2cc(F)cc(F)c2)n1C

Procedure:
The title compound was prepared according to the procedure for methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (example 16a) from 3,5-difluoro-benzoyl chloride. 1H NMR (DMSO-D6) d (ppm): 2.83 (d, 3H) 3.41 (s, 3H) 6.20 (d, 1H) 7.35 (m, 3H),
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35])=[O:2].[CH2:36](O)[CH2:37][OH:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25]([CH2:24][C:6]2([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH2:3][CH:1]3[O:38][CH2:37][CH2:36][O:2]3)[C:5]2=[O:35])=[O:26])=[CH:33][CH:32]=1
Reactant: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC3OCCO3)c3ccccc32)cc1
Yield: 68 %

Procedure:
To a solution of 0.294 g of (RS)-1-(formylmethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N′-(4-methylphenyl)ureido)indolin-2-one in 50 ml of toluene were added 0.5 ml of ethylene glycol and 10 mg of p-toluenesulfonic acid. The mixture was heated under reflux for 6 hours while azeotropically removing produced water together with toluene. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.220 g (68%) of the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH2:18][O:19][CH2:20][CH3:21].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH2:18][O:19][CH2:20][CH3:21])[N:4]([CH2:3][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])([CH3:22])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Yield: 54 %

Procedure:
1-(2-Amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine (111 mg, 0.355 mmol) was dissolved in 5 ml of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (99 μL, 0.71 mmol) and methanesulfonyl chloride (28 μL, 0.36 mmol) and the reaction was allowed to warm to ambient temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (5 mL). The organic layer was separated and washed with H2O (2×5 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure to give a tan foam. Purification by column chromatography (SiO2, 2.5%–5% MeOH/CHCl3) gave N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (75 mg) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:30])[C:10](=[C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22]2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>[O-2].[O-2].[Mn+4].ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:30])[C:10](=[C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[NH:25]2)[C:11]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH:19]=[O:20])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(C(C(=O)c1cccc(CO)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Reaction time: 4.5 h
Yield: 51.9 %

Procedure:
A 13.55 g portion of manganese dioxide was added to 20 ml of dichloromethane solution containing 2.11 g of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-[3-(hydroxymethyl)phenyl]propane-1,3-dione and stirred for 4.5 hours. After celite filtration and concentration, the thus formed residue was crystallized from hexane-ethyl acetate to obtain 1.09 g (52%) of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzaldehyde (Reference Example 10-1). FA: 405
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:16]=[CH:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+]>CS(C)=O.[I+].[Cu+]>[CH3:31][S:32]([C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:16]=[CH:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:22]=2)=[O:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1)(=[O:34])=[O:33]
Reactant: CS(=O)[O-]
Reactant: CC[C@H](NC(=O)c1cc(Br)cc2c1ccn2-c1ccc(F)cc1)c1ccc(Br)nc1
Agent: [Cu+]
Agent: [I+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC[C@H](NC(=O)c1cc(S(C)(=O)=O)cc2c1ccn2-c1ccc(F)cc1)c1ccc(S(C)(=O)=O)nc1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A microwave tube is charged with 6-bromo-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid [(S)-1-(6-bromopyridin-3-yl)-propyl]-amide (90.0 mg, 0.170 mmol, prepared as described in Example 5), copper (I) iodine (143 mg, 0.75 mmol) and sodium methanesulfinate (77 mg, 0.75 mmol) in DMSO (20 mL). The tube is capped and the solution is degassed with argon for 3 minutes. The mixture is warmed in a microwave reactor at 130° C. After 40 minutes, the reaction is diluted with saturated aqueous ammonium chloride (100 mL), saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is purified by reversed-phase HPLC to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[O:7])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C1CSCCN1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: O=C(c1cc(Br)cc(C(F)(F)F)c1)N1CCSCC1
Yield: 93.4 %

Procedure:
A solution of 3-bromo-5-(trifluoromethyl)benzoic acid (10 g), thiomorpholine (5.0 g), HOBt (7.4 g) and EDCI (9.26 g) in acetonitrile (113 ml) was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (12.3 g, yield 94%) a yellow oil.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.Cl[C:32]([F:37])([F:36])C([O-])=O.[Na+].CN(C=O)C>C(#N)C.C(OCC)(=O)C>[F:36][CH:32]([F:37])[O:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=c1c2cc(Cc3ccc(O)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1c2cc(Cc3ccc(OC(F)F)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-hydroxypyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 29, 0.025 g, 0.062 mmol) in 1 mL of acetonitrile was added sodium chlorodifluoroacetate (0.010 g, 0.068 mmol). The reaction was heated to reflux under an atmosphere of nitrogen for 4 h, and then DMF (0.310 mL) was added. The mixture was heated to 100° C. for 1 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 454.1573 for [M+H]+ [Calc'd for C24H22F2N3O4, [M+H]+=454.1573]: 1H NMR (400 MHz, CDCl6) S 8.90-8.88 (m, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.77-7.75 (m, 2H), 7.65-7.59 (m, 2H), 7.43-7.40 (m, 1H), 7.37 (t, J=73.2 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.84-4.77 (m, 1H), 4.25 (s, 2H), 4.22-4.06 (m, 3H), 3.59-3.53 (m, 1H), 3.45 (br s, 1H), 3.35-3.30 (m, 1H), 2.21-1.96 (m, 1H), 2.00-1.96 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30]C(NC5SC=C(CC(O)=O)N=5)=O)[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].N1C[CH:49]([C:51]([OH:53])=[O:52])[CH2:48]1>>[CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]5[CH2:48][CH:49]([C:51]([OH:53])=[O:52])[CH2:30]5)[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Reactant: O=C(O)C1CNC1
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(N3CC(C(=O)O)C3)n2)c(=O)[nH]c1=O

Procedure:
The title compound was prepared from the product of example 15 step (viii) (0.2 g) and 3-azetidinecarboxylic acid (0.045 g) by the method of example 7 step (i). Purification was by precipitation with ethyl acetate/isohexane and filtration. Yield 0.14 g.
Reaction SMILES: [BH4-].[Na+].[H][H].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([CH:13]([CH2:19][N+:20]([O-])=O)[CH2:14][C:15](OC)=[O:16])[CH:12]=1)#[N:6]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:6][CH2:5][C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([CH:13]2[CH2:19][NH:20][C:15](=[O:16])[CH2:14]2)[CH:12]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1cc(C#N)ccc1C
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(CN)cc1C1CNC(=O)C1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Adapting a literature known protocol (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2 6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of methyl 3-(5-cyano-2-methyl-phenyl)-4-nitro-butanoate (22b) (2.62 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS till completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are partially evaporated under reduced pressure using a rotary evaporator and the crude material is heated to 50-60° C. to complete the lactamization. Purification by silica gel column chromatography with mixtures of (MeOH) and dichloromethane (DCM) furnishes the title compound 4-[5-(aminomethyl)-2-methyl-phenyl]pyrrolidin-2-one (22c).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)[OH:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][NH:39]3)O1>>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH:11]([C:13]5[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=5)[OH:12])=[CH:8][C:6]=4[N:7]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[N:38]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CSc1ccc(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cc1
Product: CSc1ccc(C(O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)cc1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methylsulfanyl-phenyl)-methanol was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 404. (400 MHz, CDCl3): 2.52 (3H, s, CH3), 2.60 (1H, m, CH), 3.91-3.93 (4H, m, CH2), 4.09-4.11 (4H, m, CH2), 6.15 (1H, b, OH), 7.30 (1H, m, ar), 7.33 (1H, m, ar), 7.35 (1H, m, ar), 7.43 (1H, m, ar), 7.46 (1H, m, ar), 7.51 (1H, m, ar), 7.59 (1H, m, ar), 8.38 (1H, d, ar), 9.02 (1H, s, ar), 10.10 (1H, b, NH). (M+H)+ 490.27
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:40])[CH:38]=O.N1CCCCC1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:40][C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:36])[CH3:38])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Yield: 46.8 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (141 mg, 0.30 mmol, 1.0 equiv), tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate (1.12 g, 6.00 mmol, 20.0 equiv), piperidine (255 mg, 3.0 mmol, 10.0 equiv) in 1,4-dioxane (15 mL) was refluxed for 2 h. The resulting mixture was concentrated under vacuum. The residue was submitted to flash chromatography eluting with ethyl acetate to give (R)-tert-butyl (5-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)carbamate 90 mg as a pale yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CC(C)(C)C([N:11]([CH2:21][CH2:22][O:23][CH3:24])[C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][N:13]=1)=O.[NH2:27][C:28]1[C:29](=[O:42])[N:30]([CH:39]2[CH2:41][CH2:40]2)[C:31](=[O:38])[N:32]([CH2:35][CH2:36][CH3:37])[C:33]=1[NH2:34].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH:39]1([N:30]2[C:29](=[O:42])[C:28]3[NH:27][C:16]([C:15]4[CH:14]=[N:13][C:12]([NH:11][CH2:21][CH2:22][O:23][CH3:24])=[CH:20][CH:19]=4)=[N:34][C:33]=3[N:32]([CH2:35][CH2:36][CH3:37])[C:31]2=[O:38])[CH2:41][CH2:40]1
Reactant: CCCn1c(N)c(N)c(=O)n(C2CC2)c1=O
Reactant: COCCN(C(=O)C(C)(C)C)c1ccc(C(=O)O)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Oxalyl chloride (0.98 ml, 11.25 mmol, 1.05 eq) was added dropwise to a stirred solution of 6-[(2,2-Dimethyl-propionyl)-(2-methoxy-ethyl)-amino]-nicotinic acid (3 g, 10.71 mmol) in DCM (30 Ml) at 0° C. followed by one drop of DMF. Stirred at that temperature for 30 min before the addition of 5,6-Diamino-3-cyclopropyl-1-propyl-1H-pyrimidine-2,4-dione (2.4 g, 10.71 mmol, 1 eq) and followed by pyridine (0.866 ml, 10.71 mmol, 1 eq). The reaction mixture was allowed to warm to room temperature for 3 hr then the mixture was evaporated to dryness and redissolved in 30 ml of 4N NaOH. The reaction mixture was heated to reflux for a total of 5 hours. After cooling to room temperature, the pH adjusted with aqueous hydrochloric acid to 7-8. Water was evaporated to half volume then ethanol was added at 0° C. and stirred overnight (15 hr). The reaction mixture is filtered and the solid was washed with water and then ethanol. The product is then dried at 50° C. to provide 3.41 g (83%). 1H NMR (400 MHz, DMSO-d6) δ 13.68 (1H), 8.7 (1H), 8.0 (1H), 7.15 (1H), 6.6 (1H), 3.95 (2H), 3.48 (4H), 3.26 (3H), 2.6 (1H), 1.7 (2H), 1.05 (2H), 0.9 (3H), 0.7 (2H); m/z (ES+) 385.44
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[C:24](Cl)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O.N1C=CC=CC=1>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (32 mg) was dissolved in a mixture of N,N-dimethylformamide (1.0 ml) and pyridine (1.0 ml). To the solution was added octanoyl chloride (17 μl) with stirring under nitrogen atmosphere in an ice-water bath. The mixture was stirred for 2 hours under nitrogen atmosphere in an ice-water bath and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography and development was carried out with a mixture of chloroform and methanol to afford 4-formyl-6,9-dihydroxy-11-octanoyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (33 mg).