Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:14]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:17]([CH:14]([CH3:16])[CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7]
Reactant: CC(C)Nc1ccccc1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COc1ccc(C(=O)N(c2ccccc2)C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2,4-dimethoxybenzoic acid (4.31 g, 23.7 mmol) in 35 mL of dichloromethane is treated with N-isopropylaniline (3.07 mL, 21.33 mmol), hydroxybenzotriazole (3.2 g, 23.7 mmol), and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (4.54 g, 23.7 mmol). This solution is stirred at room temperature for 18 hours and the resulting solution is partitioned between ethyl acetate and 1N hydrochloride solution. The organic layer is washed with water, dried over sodium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (150 g) with 40-60% ethyl acetate/hexane as the eluent to afford 2,4-dimethoxy-N-(1-methylethyl)-N-phenylbenzamide as a colorless foam.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1)=[O:4].C([O-])(O)=O.[Na+]>CC(O)=O.O.O=[Pt]=O>[F:17][C:2]([F:1])([F:16])[C:3]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1)=[O:4]
Reactant: O=C(Nc1cncc2ccccc12)C(F)(F)F
Agent: O=[Pt]=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(NC1CNCc2ccccc21)C(F)(F)F
Reaction time: 10 h
Yield: 104.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(isoquinolin-4-yl)acetamide (1.0 g, 1.49 mmol) in AcOH (20 mL) was adde PtO2 (0.2 g) was added under nitrogen atmosphere. The reaction mixture placed under an atmosphere of hydrogen at rt for 10 h. The reaction mixture was filtered through a pad of celite, washed several times with MeOH. The filtrate was concentrated in vacuo to give a residue that was diluted with water, neutralized with NaHCO3, extracted with EtOAc (100 mL×3), the combined EtOAc layer was washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in EtOAc) to give (0.380 g, 33%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 9.72 (s, 1H), 7.24-7.07 (m, 4H), 4.98 (s, 1H), 3.89 (d, J=16.4 Hz, 1H), 3.82 (d, J=16.4 Hz, 1H), 3.10 (dd, J=4.8, 12.8 Hz, 1H), 2.88 (dd, J=6.8 Hz, 12.8 Hz, 1H), 2.50 (m, 1H). LCMS: M/z: (M+1):245
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][C:25]1[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:29]5[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[N:30]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n1
Yield: 72.3 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), 6-methylpyridine-2-carboxylic acid (66 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (100 mg, 72%) was obtained as colorless crystals.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[N:38]=[C:24]3[CH:25]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:27](=C)[CH2:28][CH2:29][N:23]3[N:22]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[F:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[N:38]=[C:24]3[CH:25]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:27](=[O:2])[CH2:28][CH2:29][N:23]3[N:22]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1
Reactant: C=C1CCn2nc(Nc3ccc(-n4ncnc4C)c(F)c3)nc2C(c2ccc(F)cc2)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnn1-c1ccc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)cc1F
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A solution of sodium periodate (2.78 g, 13.0 mmol) in water (10 mL) was added over a 10 min period via pipet to a vigorously stirred solution of the N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (1.88 g, 4.34 mmol) and osmium tetroxide (110 mg, 0.43 mmol) in THF (10.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (1.47 g, 78% yield). The crude product was used in the next step without further purification. LC-MS (M+H)+ 436.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.98 (1 H, s), 7.70 (1 H, dd, J=12.5, 2.1 Hz), 7.27-7.34 (1 H, m), 6.96-7.21 (5 H, m), 4.62 (1 H, dd, J=8.9, 3.7 Hz), 4.41-4.56 (2 H, m), 3.36 (1 H, dd, J=14.2, 9.0 Hz), 3.11 (1 H, dd, J=14.2, 3.8 Hz), 2.83-3.01 (2 H, m), 2.40 (3 H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[H][H]>C(OCC)(=O)C.CCO.O=[Pt]=O>[Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: Cc1cc(C#Cc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(CCc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Yield: 23.3 %

Procedure:
A suspension of 3-bromo-4-[(4-fluorophenyl)ethynyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (0.430 g, 1.01 mmol) in Ethyl acetate (5 mL) and EtOH (5 mL), containing PtO2 (0.015 g) was stirred in an atmosphere of hydrogen (15 psi) in a Fischer-Porter bottle for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to reduce volume. The material was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.0943 g, 22%) as a sticky semisolid after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.46 (d, 2H, J=26.4 Hz), 7.60 (d, 1H, J=8.0 Hz), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.21 (m, 2H), 6.97 (t, 2H, J=8.8 Hz), 6.24 (s, 1H), 5.43 (s, 2H), 2.93 (m, 4H), 2.31 (s, 3H); ES-HRMS m/z 401.0645/403.0603 (M+H calculated for C20H19N2OFBr requires 401.0659/403.0641).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:9]1[C:10]([CH:12]([CH3:14])[CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(C)C)ccc1C(=O)O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)C)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g, 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight. Evaporation in vacuo afforded an oil (9.27 g).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]3=[CH:23][CH:22]=[CH:21][N:9]23)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester and sodium glycinate. ESI (m/z): 360 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[NH2:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]3-nitrobenzoate (10 g) was dissolved in acetic acid (50 mL) (warming was required) and iron dust (6.92 g) was added followed by the addition of water (20 mL). There was an exothermic reaction (to 70° C.). The reaction mixture was stirred at ambient temperature for 16 hours, water (300 mL) was added and the mixture was extracted three times with ethyl acetate (100 mL each time). The combined extracts were washed consecutively with water (3×100 mL) and saturated aqueous sodium bicarbonate (2×100 mL) and dried (MgSO4). The residue obtained on removal of the solvent was filtered through silica, eluting initially with a mixture of dichloromethane and hexane (1/1 v/v) and then with dichloromethane, to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]-3-aminobenzoate, yield 8.78 g, mp 135° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCNCc1cccc(O)c1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1cccc(O)c1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-ethylaminomethyl-phenol
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]5[CH2:33][O:32]5)[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:36][NH2:37]>>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]([OH:32])[CH2:33][NH:37][CH3:36])[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Product: CNC[C@@H](O)COc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
The title compound was prepared using a similar method to that described for Example 299b from (R)-N-cyclopropyl-4-methyl-3-(3-(1-(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide (Example 299a) and methylamine.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N1CCN(C2C=C(N[C:29]([C:31]3[C:32]4[N:33]=[CH:34][CH:35]=[N:36][C:37]=4[C:38]([C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH:44]=[N:43][CH:42]=4)=[CH:39][CH:40]=3)=[O:30])C=CC=2)CC1)C>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:29]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[C:38]([C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[N:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:30])=[CH:8][CH:7]=1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CN(C)CCOc1ccc(N)cc1
Product: CN(C)CCOc1ccc(NC(=O)c2ccc(-c3cncc4ccccc34)c3nccnc23)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-isoquinolin-4-yl-quinoxaline-5-car-boxylic acid (Example 52). Title compound: ESI-MS: 464.1 [M+H]+; tR=8.23 min (System 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:28]3[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]3)[CH:15]=[CH:14][C:13]=2[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Yield: 48.6 %

Procedure:
1-(2-(1-(3,5-Dichlorophenyl)ethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (110 mg, 0.29 mmol), N,N-diisopropylethylamine (74.6 mg, 0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (77.0 mg, 49% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C25H28Cl2F3N3O3: 545.15; Observed: 568.4 (M++Na).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:40][CH3:41])[C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:42]I>CN(C=O)C>[CH2:40]([N:5]([CH2:3][CH3:4])[C:6]([C:8]1[N:9]([CH3:42])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:41]
Reactant: CI
Reactant: CCN(CC)C(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc2n1C
Reaction time: 0.25 h
Yield: 68.5 %

Procedure:
To a suspension of NaH (0.01 g, 0.36 mmol) in DMF (5ml) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid diethylamide (0.1 g, 0.18 mmol), obtained in Example 131, at 0° C., and stirred for 15 min. Methyl iodide (0.031 g, 0.216 mmol) was added to this at the same temperature. The reaction was stirred for 6 h and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-methyl-1H-indole-2-carboxylic acid diethylamide (0.07 g, 60%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][CH:32]([N:34]=[C:35]=[O:36])[CH3:33]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:35]([NH:34][CH:32]([CH3:33])[CH3:31])=[O:36])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-isopropyl-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 2-propylisocyanate (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.37 min (Grad 2); ES-MS: m/eo=484.9.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([C:9]#[C:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].C(=O)([O-])[O-].[H][H]>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:19][Si:2]([CH3:1])([CH2:9][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:6])([F:7])[F:8]
Reactant: C[Si](C)(C#CCOC1CCCCO1)CCC(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(CCCOC1CCCCO1)CCC(F)(F)F
Temperature: 25 °C

Procedure:
A suspension of compound 3 (5.00 g, 20.00 mmol) palladium hydroxide on charcoal (0.68 g, 0.21 mmol) in ethyl acetate and ethanol (100 ml, 9:1) and sodiumhydrohen carbonate (0.165 g, 1.96 mmol) were stirred at room temperature and a pressure of 100 pounds inch-2 under hydrogen for 24. The reaction mixture was filtered and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.58] to yield a colorless oil.
Reaction SMILES: C1[C@H]2CN[C@H](CO)CN2CCO1.C1[C@@H]2CN[C@H](CO)CN2CCO1.CCN(CC)CC.[CH3:32][C:33]([Si:36]([CH3:50])([CH3:49])[O:37][CH2:38][C@@H:39]1[CH2:48][N:47]2[C@H:42]([CH2:43][O:44][CH2:45][CH2:46]2)[CH2:41][NH:40]1)([CH3:35])[CH3:34]>ClCCl>[CH3:35][C:33]([Si:36]([CH3:50])([CH3:49])[O:37][CH2:38][C@@H:39]1[CH2:48][N:47]2[C@@H:42]([CH2:43][O:44][CH2:45][CH2:46]2)[CH2:41][NH:40]1)([CH3:32])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: OC[C@@H]1CN2CCOC[C@H]2CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@H]2CN1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(7S, 9aR)-octahydropyrazino[2,1-c][1,4]oxazin-7-ylmethanol and (7S, 9aS) -octahydropyrazino[2,1-c][1,4]oxazin-7-ylmethanol (D21) (315 mg,1.83 mmol) was dissolved in 10 mL of anhydrous dichloromethane and treated with Et3N (600 μL, 4.30 mmol) and TDBMSCI (590 mg, 3.91 mmol). The reaction was stirred overnight at room temperature (17 h). It was diluted with dichloromethane (30 mL) and extracted with sat. NaHCO3 (2×20 mL). TLC analysis (EtOAc: MeOH 95:5) showed 2 main products. The organics were dried and the solvent removed leaving an oil, which was purified by flash chromatography (silica, EtOAc→EtOAc:MeOH 90:10). Isolated two products: (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D22), 253 mg. Direct MS: m/z=287 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([O:20][CH3:21])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH:26][CH2:18][C:16]1[CH:15]=[C:14]([O:20][CH3:21])[C:3]([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=2)=[C:2]([F:1])[CH:17]=1
Reactant: CC(C)(C)CCN
Reactant: COc1cc(C=O)cc(F)c1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(CNCCC(C)(C)C)cc(F)c1Oc1ccc(C(N)=O)cn1
Yield: 80.1 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinamide (250 mg, 0.861 mmol), 3,3-dimethyl-butylamine (104 mg, 1.03 mmol), and NaBH4 (49 mg, 1.29 mmol) gave the title compound (259 mg) as a white solid. Mass spectrum (ion spray): m/z=376 (M+1); 1HNMR (DMSO-d6): 8.50 (s, 1H), 8.23 (d, 1 μl), 7.98 (s, 1H), 7.44 (s, 1H), 7.13 (d, 1H), 6.96 (s, 1H), 6.89 (d, 1H), 3.71 (s, 3H), 3.68 (s, 2H), 2.51 (t, 2H), 1.37 (t, 2H), 0.86 (s, 9H).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5].Br[Mg][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([F:28])[CH:22]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>O1CCCC1>[F:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[CH3:27])[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Cc1ccc([Mg]Br)cc1F
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (2.35 g, 9.10 mmol) in tetrahydrofuran (10 mL), 0.5 M solution of bromo(3-fluoro-4-methylphenyl)magnesium in tetrahydrofuran (20 mL, 10 mmol) was added dropwise under an argon atmosphere and ice cooling. Upon the completion of the dropwise addition, the mixture was stirred for 16 hours at room temperature, and then added with saturated aqueous citrate solution (40 mL). The mixture obtained was extracted with ethyl acetate (30 mL×3) and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=6/4) to give the title compound as a brown oily substance (1.35 g, yield 48%).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27]OC1C=CC(F)=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]>>[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27][O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Reactant: OCc1ccco1
Product: CCOC(=O)CCCCCCC(CCCC(O)COCc1ccco1)C(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step E, except that an equivalent quantity of furfuryl alcohol is substituted for the 4-fluorophenol of Example 1, Step E.