Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:10][C:11](OC)=[O:12])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-].OS([O-])(=O)=O.[K+]>>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Product: CC(C)(C)OC(=O)CCN(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 85.4 %

Procedure:
A solution of 7.76 g (21.43 mmol) of 3-[(3,4-dichloro-phenyl)-methoxycarbonylmethyl-amino]-propionic acid tert-butyl ester in 250 ml of ETOH was treated at 0° C. with 0.98 g (42.86 mmol) of LiBH4. The reaction was stirred 10 min at 0° C. and 15 h at RT. After cooling (0° C.) a second batch of 0.49 g (21.43 mmol) of LiBH4 was added and stirred 6 h at RT. The reaction was cooled (0° C.), neutralized with aq. 10% KHSO4 solution and extracted with EtOAc (3×). The organic phase was dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 9:1 to 1:1) to yield 6.12 g (85%) of the title compound as light yellow oil. MS: 334.2 (MH+, 2Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:29]4[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cccc(-c3cc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyridine (example E.82) (0.20 g, 0.485 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.118 g, 0.532 mmol) according to the general procedure VI. Obtained as a white solid (0.110 g, 53%). MS (ISP) 427.1 [(M+H)+] and 429 [(M+2+H)+]; mp 239° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:8][C:9]([C:11]2[C:12]([O:29][CH3:30])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:10])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[F:28][C:25]1[CH:24]=[CH:23][C:22](/[CH:21]=[CH:20]/[C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:9]([NH:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[O:10])[C:12]=3[O:29][CH3:30])[NH:16][N:15]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)C1(NC(=O)c2ccc3[nH]nc(/C=C/c4ccc(F)cc4)c3c2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(=O)NC2(C(=O)O)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a mixed solution of 200 mg of 1-({3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazol-5-carbonyl}-amino)-cyclopropane carboxylic acid methyl ester obtained in Example 1317 in 5 ml of tetrahydrofuran and 2 ml of methanol was added 2 ml of a 1N sodium hydroxide aqueous solution, followed by stirring at room temperature overnight. The reaction mixture was diluted with water and the aqueous layer was washed with diethyl ether. The aqueous layer was adjusted to pH 2 by adding 1N hydrochloric acid, and the precipitated solid was collected by filtration with glass filter. The solid was washed with water and was dried under reduced pressure, to give 151 mg of the title compound as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[C:19]([O:23][C:24]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29]([C:35]#[CH:36])([OH:34])[CH2:30]2)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:15]([C:9]1[N:8]=[C:7]2[C:6]3[CH:18]=[C:2]([C:36]#[C:35][C:29]4([OH:34])[CH2:30][CH:31]5[N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH:27]([CH2:33][CH2:32]5)[CH2:28]4)[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][N:11]2[CH:10]=1)(=[O:16])[NH2:17]
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(C#Cc1ccc3c(c1)-c1nc(C(N)=O)cn1CCO3)C2
Yield: 104.5 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure E. In a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (300 mg, 1.0 mmol) in acetonitrile (6 mL) and triethylamine (3 mL) were added Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), 3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.5 g, 2 mmol) and CuI (19 mg, 0.1 mmol). Then the solution was bubbled N2 for 5 min and microwaved for 2 h at 120° C. under nitrogen. The reaction mixture was filtered and the filtrate was purified by column (EtOAc/hexanes 2:1) to afford crude product (0.5 g, 99%). LCMS=479.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[N:16]2[N:17]=[C:18]([NH2:20])[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[Br:10][C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(Nc1nc2cccc(Br)n2n1)c1ccccc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Benzoyl chloride (4.40 g; 31.4 mmol; 2.0 eq.) was added to a suspension of 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3), 3.34 g; 15.7 mmol; 1.0 eq.) in pyridine (2.53 mL; 31.4 mmol; 2.0 eq.) and DCM (60 mL). The reaction mixture was then heated at reflux for 4 hours, after which it was cooled down to rt. Diethyl ether was added to the reaction mixture and the solid which precipitated was filtered off. The precipitate was resuspended in an aqueous mixture (pH 4/5), filtered and dried under vacuum to give the title compound as a white powder (4.97 g, quant. yield). HPLC, Rt: 2.40 min. (purity 93.4%), LC/MS, M+(ESI): 317.1, M−(ESI): 315.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:37].[N:38]12[CH2:45][CH2:44][CH:41]([CH2:42][CH2:43]1)[C@@H:40]([NH:46][C:47]([C:49]1[S:50][C:51]3[C:57](Br)=[CH:56][CH:55]=[CH:54][C:52]=3[CH:53]=1)=[O:48])[CH2:39]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:37].[N:38]12[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45]1)[C@@H:40]([NH:46][C:47]([C:49]1[S:50][C:51]3[C:57]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:56][CH:55]=[CH:54][C:52]=3[CH:53]=1)=[O:48])[CH2:39]2
Reactant: Brc1ccccc1N1CCOCC1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3N3CCOCC3)c2s1

Procedure:
100 mg (0.41 mmol) of 4-(2-bromophenyl)morpholine, 121.0 mg (0.48 mmol) of bis(pinacolato)diboron, 101.3 mg (1.03 mmol) of potassium acetate, 11.6 mg (0.02 mmol) of PdCl2(dppf), 127.6 mg (0.32 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.79 ml of 2 M sodium carbonate solution and a further 11.6 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 38.9 mg (48% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:9]([O:12][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1)[CH:10]=[CH2:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: C=CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CCOc1cc(Cl)ncn1
Temperature: 85 °C
Reaction time: 14 h
Yield: 51.5 %

Procedure:
To a solution of 7.5 g (50.3 mmol) of 4,6-dichloropyrimidine and 3.61 ml (3.07 g, 52.9 mmol) of allyl alcohol in 40 ml of dioxane were added 19.6 g (60.4 mmol) of cesium carbonate. The suspension was stirred for 14 h at 85° C. and then allowed to cool to room temperature. The solution was filtered, and the salts were washed with ethyl acetate. The filtrate was concentrated in vaccuo and purified by flash chromatography on silicagel using ethyl acetate as eluant to yield 4.42 g (25.9 mmol, 51%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O>[NH:18]([C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-Chloro-3-nitro-5-sulphamyl-benzoic acid (8.4 g), aniline (8.4 g), and water (40 ml) was stirred at 80° C for 2 hours. After the addition of 1N hydrochloric acid (50 ml) and cooling, the precipitated 4-anilino-3-nitro-5-sulphamyl-benzoic acid was collected by suction, washed with water, and recrystallized from aqueous ethanol. The melting point was 261°-262° C.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:10]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][C:13](OCC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(OCC)C>[OH:2][NH:1][C:13](=[O:14])[CH2:12][CH2:11][N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: NO
Reactant: CCOC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was added to ethyl 3-[(benzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (3.30 g; 8.8 mmol) and the resulting mixture stirred for 18 h at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×10 mL). The combined extracts were washed with saturated aqueous NaCl (1×10 mL), dried over MgSO4, and evaporated under reduced pressure to give a crude gum. Trituration with diethyl ether afforded 2.33 g (68%) of the title compound as an off-white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.06 (m, 2H), 3.25 (m, 2H), 3.87 (s, 3H), 4.33 (s, 2H), 7.16 (d, 2H), 7.20-7.42 (m, 5H), 7.80 (d, 2H), 8.70 (bs, 1H), 10.38 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O.CCO.C([O-])(O)=O.[Na+]>CC(O)=O.[Fe]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCOc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(CCOc2ccc(N)c3ccccc23)ccn1
Temperature: 25 °C
Yield: 103.8 %

Procedure:
A mixture of tert-butyl 4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (21) (5.20 g, 12.7 mmol) and iron mesh (4.30 g, 76 mmol) was suspended in AcOH and EtOH (1:2, 120 mL) and was heated to 60° C. and stirred rapidly until the reaction was judged to be complete by LC-MS. The mixture was cooled to RT, poured carefully onto saturated aq NaHCO3 solution (1000 mL) and extracted with EtOAc (500 mL×2). The combined organic layers were washed with saturated aq NaHCO3 solution (1000 mL), water (1000 mL), brine (1000 mL) and dried. The solution was filtered and evaporated in vacuo to give the title compound (22) as a yellow oil (5.00 g, 95%): m/z 380 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:21][C:22](=[S:30])[NH:23][CH2:24][CH2:25][O:26]C(=O)C)[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Li+].C(OCC)(=O)C>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:21][C:22]([NH:23][CH2:24][CH2:25][OH:26])=[S:30])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)OCCNC(=S)NC(Cc1cc(C)cc(C)c1)c1cccc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(CC(NC(=S)NCCO)c2cccc3c2CCCC3)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of acetic acid 2-{3-[2-(3,5-dimethyl-phenyl)-1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-ethyl]-thioureido}-ethyl ester (2.60 g) in THF (30 ml) was added a solution of lithium hydroxide (294 mg) in water (30 ml) and the mixture stirred for 6 hours at room temperature. The reaction mixture was poured into ethyl acetate (300 ml) and washed with potassium carbonate solution (5 wt % in water). The solution was dried over sodium sulphate. Removal of the solvent in vacuo yielded 1-[2-(3,5-dimethylphenyl)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)-ethyl]-3-(2-hydroxyethyl)-thiourea in 2.28 g (97%) yield.
Reaction SMILES: C(O)(=O)C(O)=O.C([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]([CH2:30][C:31]1[CH:36]=[C:35]([Br:37])[C:34]([O:38][CH3:39])=[C:33]([Br:40])[CH:32]=1)[NH:20][CH2:19][CH2:18]2)C1C=CC=CC=1.[ClH:41]>CO>[ClH:41].[Br:40][C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([Br:37])[C:34]=1[O:38][CH3:39])[CH2:30][CH:21]1[C:22]2[C:17](=[CH:16][C:15]([OH:14])=[C:24]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: COc1c(Br)cc(CC2NCCc3cc(OCc4ccccc4)c(NS(C)(=O)=O)cc32)cc1Br
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COc1c(Br)cc(CC2NCCc3cc(O)c(NS(C)(=O)=O)cc32)cc1Br

Procedure:
A solution of N-[6-benzyloxy-1-(3,5-dibromo-4-methoxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-methanesulfonamide oxalate (3.98 g, 0.0057 mol) in a mixture of conc. HCl (50 mL) and methanol (50 mL) was refluxed for 1h, cooled and concentrated. A residue was crystallized from methanol—ethyl ether mixture. Yield 2.75 g (87%), M.p. 244-245° C. (dec.). 1H NMR (300 MHz, DMSO) δ 2.9 (s, 3H), 2.95-3.22 (m, 4H), 3.25-3.45 (m, 2H), 3.79 (s, 3H), 4.67 (m, 1H), 6.75 (s, 1H), 7.15 (s, 1H), 7.79 (s, 2H), 8.84 (s, 1H), 9.26 (d, J=12.6 Hz, 2H), 10.18 (s, 1H). Anal. (C18H21Br2ClN2O4S) calcd., C 38.83, H 3.80, N 5.03; found C 38.91, N 4.83.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=3)[CH:22]=[O:23])[N:15]=2)[NH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:16]2=[N:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH2:22][OH:23])[CH:24]=3)=[CH:13][N:12]=[C:11]2[NH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-methoxybenzaldehyde (27.2 mg, 0.076 mmol) in MeOH (1 mL) was added NaBH4 (2.86 mg, 0.076 mmol). The mixture was stirred at room temperature for one hour, and then concentrated under reduced pressure. The residue thus obtained was purified by column chromatography [silica gel; MeOH/DCM (1:19)] to give the product as an off-white powder (22 mg, 80%). 1H NMR (400 MHz, DMSO): δ 8.35 (s, 1H), 8.01 (s, 1H), 7.84 (dd, J=2.0, 8.8 Hz, 1H), 7.40-7.25 (m, 5H), 7.02 (d, J=8.4 Hz, 1H), 5.04 (s, 2H), 4.52 (d, J=5.2 Hz, 2H), 3.81 (s, 3H). MS: 363.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH:14]([CH3:15])[CH2:13][O:12][CH2:11][CH:10]2[CH3:16])[N:3]=1.[CH3:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH:14]([CH3:15])[CH2:13][O:12][CH2:11][CH:10]2[CH3:16])[N:3]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][CH3:17])=[O:20])=[CH:27][CH:26]=2)[N:7]=1
Reactant: CC1COCC(C)N1c1nc(Cl)nc(Cl)n1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3C(C)COCC3C)n2)cc1
Yield: 16 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 1.15 g, 16% yield.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]3[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[C:16]([CH2:36][CH3:37])=[N:15]2)=[C:9]([CH3:38])[CH:8]=1.O>O1CCCC1>[CH3:13][C:11]1[CH:12]=[CH:7][CH:8]=[C:9]([CH3:38])[C:10]=1[N:14]1[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]2[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[C:16]([CH2:36][CH3:37])=[N:15]1
Reactant: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cccc2C)c1CC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of n-butyl lithium (2.5 M hexane solution; 0.028 ml, 0.071 mmol) chilled to -78° C., a solution of (R)-2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-3-ethoxymethyl-1,2,3,4-tetrahydro-isoquinoline (33 mg, 0.065 mmol) in anhydrous tetrahydrofuran (0.1 ml) was added dropwise. After stirring at -78° C. for 10 minutes, water (0.1 ml) was added. The resulting mixture was warmed to room temperature and stirred for 20 minutes. The reaction was quenched by addition of aqueous ammonium chloride (1 ml), and then extracted with ethyl acetate/water (5 ml of each). The separated organic extract was washed with an equal volume solution of aqueous ammonium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil (17 mg). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:5 in volume) afforded the title compound (2 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:9])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:27][C:28]1[N:37]=[C:36]([C:38]([N:40]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41]2)=[O:39])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:49]3[CH:54]=[C:53]([F:55])[C:52]([F:56])=[CH:51][C:50]=3[CH2:57]Cl)[CH:34]=2)[N:29]=1>C(#N)C>[P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])([O:9][CH2:57][C:50]1[CH:51]=[C:52]([F:56])[C:53]([F:55])=[CH:54][C:49]=1[C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([NH2:27])[N:37]=[C:36]2[C:38]([N:40]1[CH2:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:48]1)=[O:39])=[O:5]
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Reactant: CCOP(=O)([O-])OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CCOP(=O)(OCC)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C

Procedure:
800 mg of tetrabutylammonium diethylphosphate are added to 270 mg of [2-amino-6-(2-chloromethyl-4,5-difluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 20 ml of acetonitrile, and the solution obtained is heated at 80° C. for 2 h. After cooling to 25° C., undissolved material is filtered off, and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C@@H:10]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:25].C([O-])(=O)C.[K+].[N:31](OCCC(C)C)=O.C(=O)(O)[O-].[Na+].C(NCC)C.CCCCCCC>C(O)C.C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15]([C@H:10]([CH2:9][C:5]1[CH:6]=[C:7]2[C:2](=[C:3]([CH3:25])[CH:4]=1)[NH:1][N:31]=[CH:8]2)[C:11]([O:13][CH3:14])=[O:12])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
(R)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)propanoate (50.0 g, 140 mmoles) was weighed into a flame-dried 5 L three neck round bottom flask, followed by the addition of toluene (2.4 L) and glacial acetic acid (120 mL, 2.1 moles). The mixture was mechanically stirred to form a clear solution, and then potassium acetate (103 g, 1.05 moles) was added. To the resulting white suspension, iso-amyl nitrite (20.7 mL, 154 mmoles) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 16 h. Saturated sodium bicarbonate (1 L) was added, followed by the careful addition of solid sodium bicarbonate to neutralize the acetic acid. The mixture was extracted with a mixture of dichloromethane (2 L) and brine (1.5 L). After separation, the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. Solvents were removed to afford a tan solid, which was washed with hexanes (2 L) and toluene (150 mL). The solid was recrystallized from hot acetone (260 mL) and hexanes (700 mL). The slightly cloudy mixture was allowed to cool to room temperature slowly, then to 0° C. for 1.5 h, and finally to −15° C. for 1.5 h. The resulting solid was filtered and washed with ice-cold acetone/hexanes (1:1, 200 mL) to afford 39.1 g (76% yield). Analytical HPLC showed >98% UV purity. The enantiomeric excess (ee) was determined to be 99.8% (conditions: Chiralpak AD column, 4.6×250 mm, 10 μm; A=ethanol, B=0.05% diethylamine/heptane; 85% B @1.0 mL/min. for 55 min. The retention times for R was 44.6 min and for S was 28.8 min) 1H-NMR (DMSO-d6) δ 2.48 (s, 3H), 2.93 (dd, J=13.4, 10.7 Hz, 1H), 3.10 (dd, J=13.7, 4.9 Hz, 1H), 3.63 (s, 3H), 4.32-4.27 (m, 1H), 4.97 (s, 2H), 7.03 (s, 1H), 7.24-7.22 (m, 2H), 7.29-7.27 (m, 3H), 7.41 (s, 1H), 7.83 (d, J=8.2Hz, 1H), 7.99 (s, 1H), 13.1 (s, 1H); 13C-NMR (DMSO-d6) δ 16.7, 36.5, 51.8, 56.0, 65.3, 117.6, 119.6, 122.7, 127.2, 127.4, 127.6, 128.2, 129.3, 133.4, 136.8, 139.2, 155.9, 172.4. Mass spec.: 368.16 (MH)+.