Azzindani/Open_Reaction_Data huggingface dataset:
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:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[NH:11][C:10]=2[CH:20]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:17]1([C:15]([NH:14][C:12]2[NH:11][C:10]3[CH:20]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)[CH:7]=[CH:8][C:9]=3[N:13]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1H-benzimidazol-2-yl]cyclopropanecarboxamide (159 mg, 516 μmol) and 3-(trifluoromethyl)benzoic acid (191 mg, 1.01 mmol) in pyridine (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (375 mg, 1.96 mmol) and N,N-dimethylpyridine-4-amine (18.5 mg, 151 μmol), and the mixture was stirred at room temperature for 12 hr. Methanol (5 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr and concentrated under reduced pressure. The residue was diluted with methanol (1 mL) and ethyl acetate (30 mL), washed with 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→80/20), and the obtained crude crystals were recrystallized from acetone and diisopropyl ether to give the title compound (135 mg, 54%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:15][C:14](=[O:16])[CH2:13][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:8]([CH2:26][C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[C:7]=2[CH3:12])=[CH:22][CH:21]=1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OCc1ccc(Cl)cc1)c(C)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-methoxy-2-methyl-3-indoleacetic acid (4 g, 18.3 mmol) in anhydrous DMF (20 mL) at 0°-5° C. was added NaH (1.6 g, 60% dispersion in oil, 40 mmol) and stirred at room temperature for 40 min., then cooled again to 0°-5° C., and treated with 4-chlorophenylmethyl chloride (5.9 g, 36.6 mmol) and let stand at room temperature overnight. Water (50 ml) was added and the mixture was extracted with ethylacetate (100 mL), washed with brine and dried (MgSO4), evaporated in vacuo, and purified by chromatography (silica gel, 10% ethylacetate in pentane) to yield 1-(4-chlorophenylmethyl)-5-methoxy-2-methyl-3-indoleacetic acid 4-chlorophenylmethyl ester.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To the solution of (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 682 mg (3.55 mmol) in tetrahydrofuran 2 ml, 1-naphthaldehyde 554 mg (3.55 mmol) was added and stirred at room temperature for 0.5 hour. The reaction mixture was diluted with tetrahydrofuran 3 ml and sodium triacetoxyborohydride 829 mg (3.91 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate aq. 50 ml twice, water 50 ml twice and brine 50 ml twice. The organic phase was dried with magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 685 mg (67.1%).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]1=[O:11]>>[CH3:3][N:4]1[CH:9]=[C:8]([Br:1])[C:7]([CH3:10])=[N:6][C:5]1=[O:11]
Reactant: Cc1ccn(C)c(=O)n1
Reactant: BrBr
Product: Cc1nc(=O)n(C)cc1Br
Reaction time: 3 h
Yield: 40 %

Procedure:
Bromine (0.012 mol) was added to an aqueous solution (100 ml) of 1,4-dimethylpyrimid-2-one (0.008 mole) and the reaction mixture left at room temperature for 3 hr before freeze-drying. The residual material was triturated with acetone and recrystallised from water; yield 40%, m.p. 170° C. (decomp.). (Found: C, 25.5; H, 2.9. Calc. for C6H7BrN2O HBr: C, 24.4; H, 2.8).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC1CC(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.28 g (0.001 mole) of (rac)-2-chloro-9-cyclopentyl-8-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 2 mL of N,N-dimethylacetamide and 0.093 mL (0.0015 mole) of iodomethane at 0 degrees was added 0.06 g (0.0015 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 10 mL of water was added. The precipitate collected by filtration to give 0.278 g of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3) as an yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([NH2:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[C:29]([NH:48][C:49]1[S:50][CH:51]=[C:52](/[C:54](=[N:67]/[O:68][CH2:69][CH2:70][CH2:71][CH3:72])/[C:55](ON2C3C=CC=CC=3N=N2)=[O:56])[N:53]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.C(NC1SC=C(/C(=N/OC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(NC(=O)C)N=NN=4)CS[C@H]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC(N(C)C)=O>[C:29]([NH:48][C:49]1[S:50][CH:51]=[C:52](/[C:54](=[N:67]/[O:68][CH2:69][CH2:70][CH2:71][CH3:72])/[C:55]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]4[N:15]([NH2:16])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:56])[N:53]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 33.6 %

Procedure:
A solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.653 g, 2 mmol), triethylamine (0.405 mg, 4 mmol) and 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-n-butoxyiminoacetate (1.32 g, 2.2 mmol) in dimethylacetamide (6 ml) and water (0.6 mol) was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-n-butoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.535 g, 33.6%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Br:17])=[C:15]([Br:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Br:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Br:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Br)c(Br)n(Cc3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dibromo-7-cyano-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 525 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([Si](C)(C)C)=[C:4]([F:15])[CH:3]=1.[I:16]Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([I:16])=[C:4]([F:15])[CH:3]=1
Reactant: ClI
Reactant: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 162.5 %

Procedure:
A solution of 6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde (600 mg, 2.4 mmol) in methylene chloride (7 mL) was cooled to 0° C. and treated with solution of iodochloride (780 mg, 4.8 mmol) in methylene chloride (10 ML) and stirred at ambient temperature for 2 hours. Additional iodochloride (900 mg) was added and the solution heated under reflux for 40 minutes. The solution was allowed to cool and was washed with sodium bisulfite (15 ml, 5% solution), water (10 mL), and a saturated solution of sodium bicarbonate (10 mL). The organic phase was dried (sodium sulfate) and concentrated to give 6-chloro-2,4-difluoro-3-iodobenzaldehyde (620 mg, 3.9 mmol): LC/MS (m/z=302).
Reaction SMILES: [CH2:1]([N:3]([C:8]1[N:13]2[N:14]=[C:15]([CH2:26][O:27]C)[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]2[CH2:29][CH2:30][CH2:31][C:9]=12)[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([N:3]([C:8]1[N:13]2[N:14]=[C:15]([CH2:26][OH:27])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]2[CH2:29][CH2:30][CH2:31][C:9]=12)[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCCN(CC)c1c2c(nc3c(-c4ccc(OC)cc4C)c(COC)nn13)CCC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCN(CC)c1c2c(nc3c(-c4ccc(O)cc4C)c(CO)nn13)CCC2
Temperature: -30 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
To a solution of the compound prepared in Example 2(1) (506 mg) in methylene chloride (14 ml) which was cooled to −78° C., 1M boron tribromide in methylene chloride (12 ml) was added. The mixture was stirred for 30 minutes at −78° C. and for 5 hours at −30° C. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and the resultant solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1→2:3) to give the title compound (303 mg) having the following physical data
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:12])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:13]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:12])[C:8]=1[C:9]([O:11][CH3:13])=[O:10]
Reactant: CO
Reactant: COc1cccc(O)c1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(O)cccc1OC

Procedure:
A mixture of 6-methoxysalicylic acid (10.0 g, 59.5 mmol) in methanol (40 mL) and sulfuric acid (2 mL) is heated at reflux 48 h. Although some acid remains the reaction is concentrated to remove the methanol and partitioned between ethyl acetate and saturated sodium carbonate solution. The organic phase is separated and washed with sodium carbonate until no acid remains by TLC analysis. The organic phase is dried and concentrated to provide the title compound as a low melting solid.
Reaction SMILES: COC1C=CC(/C=C2/C(NC(S/2)=N)=O)=CC=1OC1CCCC1.C(O[Na])(C)=O.[O:28]=[C:29]1[C:33](=[CH:34][C:35]2[N:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[CH:38]3)[S:32][C:31]([NH:47]CC2SC=CC=2)=[N:30]1>CC(O)=O>[NH2:47][C:31]1[S:32][C:33](=[CH:34][C:35]2[N:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[CH:38]3)[C:29](=[O:28])[N:30]=1
Reactant: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Agent: CC(=O)O[Na]
Agent: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(N)=NC3=O)nc2c1
Temperature: 120 °C
Yield: 51.3 %

Procedure:
To a mixture of pseudothiohydantoin (Aldrich, 97%, 23.2 mg, 0.20 mmol), AcONa (160 mg, 1.95 mmol), molecular sieves, and 6-formyl-[1,5]naphthyridine-3-carbonitrile (38.5 mg, 0.21 mmol) (see Example 11) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 120° C. for 3.5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, AcOEt and ether to give 6-(2-amino-4-oxo-4H-thiazol-5-ylidenemethyl)-[1,5]naphthyridine-3-carbonitrile as a yellowish solid (30.3 mg, 44.6%). LR-ES (+) m/e 282 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].I.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[N:27]=[N:28][CH:9]=2)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(=N)NN)cc1
Reactant: O=CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: I
Product: COc1ccc(-c2nncc(-c3ccc(F)c(C(F)(F)F)c3)n2)cc1

Procedure:
(4-Fluoro-3-trifluoromethylphenyl)oxoacetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (2.37 g, 8.08 mmol) using the method described in Example 1 to give 5-(4-fluoro-3-trifluoromethylphenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine as a yellow solid (1.13 g): δH (400 MHz, CDCl3) 3.92 (3H, s), 7.06-7.10 (2H, m), 7.44 (1H, t, J 9.2 Hz), 8.44-8.49 (1H, m), 8.56 (1H, dd, J 2.0, 6.7 Hz), 8.58-8.62 (2H, m), 9.54 (1H, s); m/z (ES+) 350.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (19 mg, 0.04 mmol) in dry DMF (1 mL) was added sodium hydride (8 mg, 0.18 mmol) at 0° C. under nitrogen. After 1 h at 0° C., 2-chloro-N,N-dimethylethanamine.hydrochloride (18 mg, 0.12 mmol) was added and the resulting mixture was stirred for an additional 5 h at 40° C. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 3% MeOH in dichloromethane) to give the title compound (7 mg, 32%). 1H NMR (500 MHz, CDCl3): 7.38 (1H, s), 7.31-7.24 (7H,m), 7.20-7.18 (2H,m), 5.01 (1H, br s), 4.88 (2H, s), 4.08 (2H,t), 2.60 (2H, t), 2.55-2.25 (4H, m), 2.33 (6H, s), 2.09-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([N:9]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.CCOC(C)=O>[NH2:3][CH2:2][CH2:1][NH:4][C:12]1[C:13](=[O:14])[N:9]([C:5]([CH3:7])([CH3:6])[CH3:8])[S:10](=[O:23])(=[O:22])[C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCCN)=C(c2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Ethylenediamine (0.60 g, 10.0 mmol) was dissolved in dry DMF (50 ml) and heated to 60° C. 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.00 g, 3.34 mmol) dissolved in DMF (10 ml) was added dropwise over 30 mins and stirred at 60° C. for 10 mins. The reaction mixture was diluted with EtOAc (300 ml) and washed with water (400 ml and 2×200 ml), dried (Na2SO4), filtered and evaporated to give the title compound (0.97 g, 90%). 1H-NMR (500 MHz, CDCl3): δ 7.50-7.45 (m, 2H), 7.42-7.37 (m, 3H), 5.83-5.76 (m, 1H), 2.84-2.78 (m, 2H), 2.67-2.62 (m, 2H), 1.71 (s, 9H); 13C-NMR (125 MHz, CDCl3): δ 159.7, 135.4, 131.6, 129.5, 128.6, 125.2, 106.9, 61.5, 46.2, 40.8, 27.7; Mass Spectrum: M+H+ 324.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:27](S(C3C=CC(C)=CC=3)(=O)=O)[C:18]3=[N:19][CH:20]=[C:21]4[CH:25]=[N:24][N:23]([CH3:26])[C:22]4=[C:17]3[CH:16]=2)=[CH:3]1.[OH-].[Na+].[Li+].[OH-]>O1CCOCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[NH:27][C:18]3=[N:19][CH:20]=[C:21]4[CH:25]=[N:24][N:23]([CH3:26])[C:22]4=[C:17]3[CH:16]=2)=[CH:3]1
Reactant: COC(=O)c1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)O)ccc21
Temperature: 85 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a flask was added methyl 1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylate (0.42 g, 0.82 mmol, prepared using D from Preparation #1 with methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carboxylate [Preparation #19]) and NaOH (0.30 g, 7.5 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The mixture was heated to about 85° C. After about 1 h, LiOH (0.196 g, 8.18 mmol) was added and heating was continued at about 100° C. for about 5 h. The mixture was cooled and concentrated under reduced pressure to remove most of the organics. The mixture was diluted with water (30 mL) then adjusted to about pH 4 with AcOH. The mixture was filtered and the solids washed with water (5 mL). The solids were dried to a constant weight under vacuum at about 60° C. to give 1-methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylic acid the title compound (0.17 g, 60%): LC/MS (Table 2, Method a) Rt=1.73 min; MS m/z 346 (M+H)+. Syk IC50=A.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.CCOC(C)=O.CN(C=O)C>[CH2:25]([NH:32][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 128.4 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzo-triazole hydrate (42.7 mg, 0.316 mmol), benzylamine (45 mg, 0.42 mmol) in anhydrous THF (5 ml) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol). The resulting mixture was allowed to stir at RT. After 20 min, DMF (2ml) was added to the reaction mixture and the mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (97 mg, 99%): m.p. 113-115° C.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[NH:9][CH2:8][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:32]
Reactant: CCCCN(CCCC)CCC(CN)(c1ccccc1)c1ccccc1
Reactant: CCOC(N)=O
Product: CCCCN(CCCC)CCC(CNC(=O)OCC)(c1ccccc1)c1ccccc1

Procedure:
From 2,2-diphenyl-4-di-n-butylaminobutyl-amine in analogy to 3a. The crude urethane was further reacted in a crude state.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH2:31]([Mg]Br)[CH:32]([CH3:34])[CH3:33]>C1COCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH:25]([OH:26])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][CH3:28])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CC(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (1.755 mmol) (Example 91, Step C) in THF (5 mL) at 0° C. was added 2 M isobutylmagnesium bromide (878 μL, 1.742 mmol) under N2. The reaction was allowed to warm to rt. After being stirred for 2 h at rt, the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed (sat. aq. NaCl solution), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by the flash chromatography on silica gel (eluent: 15 to 35% EtOAc/Hexane, gradient elution) to provide the title compound as a mixture of two diastereomers.