Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[C:5]([CH3:8])=[CH:6][CH:7]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:8][C:5]1[C:4]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2cc(F)ccc2CBr)OC1(C)C
Temperature: 25 °C
Yield: 84 %

Procedure:
3-Fluoro-6-methylphenylboronic acid pinacol ester (29a, 5.01 g, 21.2 mmol) and 140 ml CCl4 were placed in 500 ml round-bottom flask. NBS (3.97 g, 22.3 mmol, 1.05 eq) and AIBN (0.054 g, 0.33 mmol, 0.016 eq) were added and the reaction mixture was refluxed for 3.5 h in the presence of 75 W incandescent bulb. After 3.5 h the solution was cooled down to room temperature allowing the succinimide to precipitate out. The solid was filtered off. The solvent was removed and oily product was collected. Purification with column chromatography (95/5 Hexanes/Ethyl acetate) resulted in pure product (30a, 5.59 g, 84% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(Br)c(F)cc2N1
Solvent: Cc1ccccc1
Product: Fc1cc2c(cc1Br)CCC(=S)N2
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroquinolin-2(1H)-one (122-3; 13 g, 0.02 mol) in toluene (50 mL) was added Lawesson's reagent (21.54 g, 0.0532 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 261.88.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH2:60][F:61])[C:57](=[O:62])[CH2:56][O:55][C:54]=4[N:63]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH2:60][F:61])[C:57](=[O:62])[CH2:56][O:55][C:54]=4[N:63]=3)=[CH:48][CH:49]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CO4)cc2)CCC1
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CO4)cc2)CCC1
Yield: 104.3 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(2-fluoroethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (60 mg, 0.116 mmol) was reacted to afford the title compound (50.5 mg). 1H NMR (500 MHz, CH3OD) 7.69 (1H, s), 7.42 (2H, d), 7.38 (2H, d), 7.30 (3H, m), 7.22 (2H, m), 4.99 (2H, s), 4.80 (1H, t), 4.70 (1H, t), 4.40 (1H, t), 4.35 (1H, t), 2.73-2.79 (2H, m), 2.54-2.60 (2H, m), 2.20-2.25 (1H, m), 1.95-1.97 (1H, m). LCMS (Method D): RT=0.83 min, M+H+=418.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12].OC1C2N=NNC=2C=CC=1.[OH:33][CH:34]([CH:37]1[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]1)[CH2:35][NH2:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:33][CH:34]([CH:37]1[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]1)[CH2:35][NH:36][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([S:11](=[O:13])(=[O:12])[NH:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:15][CH:16]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3c(F)cc(F)cc3F)cc2)O1
Temperature: -10 °C
Reaction time: 10 h

Procedure:
4.97 g (15 mmol) of 4-[N-(2,4,6-trifluorophenyl)sulfamoyl]-benzoic acid is dissolved in 50 ml of dry dimethylformamide under argon atmosphere, 2.03 g (15 mmol) of hydroxybenzotriazole and 2.42 g (15 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine are added and the solution is cooled to -10° C. At this temperature, 3.09 g (15 mmol) of dicyclohexylcarbodiimide is added to the solution. Then it is stirred for 1 hour at -10° C. and 10 hours at room temperature. The turbid reaction solution is filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is dissolved in 100 ml of ethyl acetate, the solution is shaken out five times with saturated sodium bicarbonate solution and twice with water, the organic phase is dried on sodium sulfate, filtered and concentrated by evaporation. 3.46 g (7.29 mmol)=48.6% of the theoretical yield is obtained as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[CH2:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
60% Sodium hydride dispersion in oil (4.4 g, 0.11 mol) was added in portions over 15 minutes to a stirred solution of 4-chloro-2-nitrophenol (17.4 g, 0.10 mol) in dimethylformamide (200 ml) at 0°-5° C. The mixture was stirred for 15 minutes then benzyl chloride (12.7 g, 0.10 mol) was added dropwise over 5 minutes. The mixture was stirred for 5 days at room temperature, diluted with water and extracted with ether. The extract was washed three times with water, dried and evaporated and the residue was triturated with petroleum spirit.
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:20](=O)(OC(Cl)(Cl)Cl)[O:21]C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([F:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(Br)cccc1NC(=O)c1cccc(F)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide (5.70 g, 17.6 mmol) in THF (100 mL) was treated with bis(trichloromethyl) carbonate (triphosgene) (6.28 g, 21.2 mmol) at room temperature and stirred for 15 min. The mixture was diluted with EtOAc, carefully treated with saturated aqueous NaHCO3 and stirred at room temperature until gas evolution stopped. The separated organic phase was washed sequentially with saturated aqueous NaHCO3, water and brine, and was dried and concentrated. The residue was triturated with ether to provide 3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as an off-white solid (6.00 g, 97% yield). Mass spectrum m/z 349, 351 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.59 (d, J=17.6 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.70 (dd, J=7.8, 1.2 Hz, 1H), 7.54-7.43 (m, 1H), 7.28-7.21 (m, 2H), 7.21-7.17 (m, 1H), 2.28 (s, 3H).
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].CS([C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])=O>>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:20]2[NH:21][CH:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Agent: Cl
Product: N=C(N)Nc1nc(CCCCNc2[nH]ccc2[N+](=O)[O-])cs1

Procedure:
The title compound is prepared from 4-(2-guanidino-4-thiazolyl)butylamine dihydrochloride and 2-methylsulphinyl-3-nitropyrrole by a process analogous to that described in Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH:15]([OH:17])[CH3:16].[CH3:19]I>CCOC(C)=O.[Ag]=O>[CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH:15]([O:17][CH3:19])[CH3:16]
Reactant: COCC1C(=O)OC1CCCCC(C)CC(C)O
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)OC
Temperature: 60 °C

Procedure:
10 mg of 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanol in 1 ml of EtOAc was added a small amount of activated silver oxide and 0.5 ml of methyl iodide. The mixture was heated for 5.5 hours at 60° C. The solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash chromatography to yield 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-methoxyoctane. ##STR13##
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12](COCC[Si](C)(C)C)[CH:11]=2)[CH:7]=[N:6]1.FC(F)(F)C(O)=O.N>>[CH3:47][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cnn(CCN(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 81.3 %

Procedure:
(S)-2-(1-((5-(1-(2-(Dimethylamino)ethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.04 mmol) was treated with trifluoroacetic acid (1.5 mL, 19.47 mmol) and a solution of ammonia (7N in methanol, 2 mL, 14 mmol) according to the method described in Example 27 to give 17 mg (74% yield) of the title compound. Purity 99%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
A suspension of 5-bromo-1H-indazole (200 mg, 1.02 mmol), cesium carbonate (661 mg, 2.00 mmol), and iodomethane (156 mg, 1.10 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 h. The mixture was partitioned between 5% lithium chloride and ethyl acetate, the aqueous layer was extracted with ethyl acetate (2×), the combined organic extracts were washed with 1 N sodium hydroxide, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica (hexanes/ethyl acetate 4:1) gave 5-bromo-1-methyl-1H-indazole (150 mg, 70% yield) as an orange solid. MS (EI) for C8H7BrN2: 212 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH:5]([O:35][CH2:36][CH3:37])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH:31]2[CH2:33][CH2:32]2)[C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH3:34])C.[Li+].[OH-]>>[CH:31]1([CH:14]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:35][CH2:36][CH3:37])[C:4]([OH:38])=[O:3])=[C:8]([CH3:34])[CH:9]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)C(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 3-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 3-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid as a mixture of two diastereomeric racemates as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=4)[CH:11]=[C:10]([CH3:22])[N:9]=3)[CH:3]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-(4-Chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.45 g), which was subsequently deprotected.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][C:21]1[CH:20]=[CH:19][C:18]([NH:27][C:28]3[N:33]=[C:32]([NH:34][C:35]4[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=4[C:37]([NH:39][CH3:40])=[O:38])[C:31]([Cl:45])=[CH:30][N:29]=3)=[CH:17][C:16]2=1.[CH3:46][C:47]([CH3:49])=O.ClC(Cl)C>C(O)(=O)C>[Cl:45][C:31]1[C:32]([NH:34][C:35]2[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=2[C:37]([NH:39][CH3:40])=[O:38])=[N:33][C:28]([NH:27][C:18]2[CH:19]=[CH:20][C:21]3[CH2:22][CH:23]4[N:26]([CH:47]([CH3:49])[CH3:46])[CH:15]([CH2:25][CH2:24]4)[C:16]=3[CH:17]=2)=[N:29][CH:30]=1
Reactant: CC(C)=O
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2C(C)C)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
Sodium triacetoxyborohydride (100 mg, 0.47 mmol) was added to a solution of 2-[2-(12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (100 mg, 0.23 mmol), acetone (0.034 mL, 0.47 mmol), acetic acid (1 drop) and dichloroethane (5 mL). The reaction was stirred at room temperature for 18 h. The reaction was then quenched with saturated aqueous NaHCO3 (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated to afford the title compound as off-white solid (89 mg, 82%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.3 (s, 1H), 8.8-8.7 (m, 2H), 8.2 (s, 1H), 7.8 (d, 1H, J=7.8 Hz), 7.5 (appt t, 1H, J=8.1 Hz), 7.4 (d, 1H, J=8.6), 7.3 (s, 1H), 7.1 (appt t, 1H, J=7.6 Hz), 6.9 (d, 1H, J=8.3 Hz), 3.9 (m, 1H), 3.6 (m, 1H), 3.0 (dd, 1H, J=17.2, 4.6 Hz), 2.8 (d, 3H, J=4.3 Hz), 2.4 (m, 1H), 2.2 (d, 1H, J=17.2 Hz), 2.1-2.0 (m, 2H), 1.6 (m, 1H), 1.5 (m, 1H), 1.1 (d, 3H, J=5.9 Hz), 0.9 (d, 3H, J=5.9 Hz); MS (m/e) 477 (M+1); mp 202-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:26])[CH:17]=[C:18]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:13]3=[N:12][C:11]=2[CH3:27])O)=[C:4]([F:28])[CH:3]=1.ClCCCl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>CO>[Cl:26][C:16]1[CH:17]=[C:18]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:13]2[N:14]([C:10]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:28])=[C:11]([CH3:27])[N:12]=2)[N:15]=1
Reactant: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(O)c1ccc(Cl)cc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1Cc1ccc(Cl)cc1F
Temperature: 70 °C
Yield: 93.6 %

Procedure:
Combine (4-chloro-2-fluorophenyl)(6-chloro-2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-3-yl)methanol (0.4 g, 0.94 mmol), 1,2-dichloroethane (25 mL), triethylsilane (0.45 mL, 3 equiv.), and trifluoroacetic acid (0.57 mL, 8 equiv.) in a round bottom flask and place under nitrogen. Heat at 70° C. overnight. Concentrate reaction in vacuo. Load onto a Varian MegaElut® 10 gram SCX ion exchange cartridge (prewashed with methanol). Elute with methanol to remove non-basic impurities. Elute with 2 M ammonia in methanol. Concentrate in vacuo to give the title compound (0.36 g, 94%). LCMS (4 min)=409.0, 411.0, M+1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[I-:23].[Na+].CNCCNC>[Cu](I)I.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:23])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Reactant: [I-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cc(OCc2ccccc2)ccc1I
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a mixed solution of 4-(benzyloxy)-1-bromo-2-fluorobenzene (187 g, 665 mmol) described in Production Example 1-2-4 and 1,4-dioxane (300 mL) were added copper iodide (I) (12.6 g, 66.1 mmol), sodium iodide (200 g, 1.33 mol) and N,N′-dimethylethylenediamine (14.0 mL, 132 mmol) at room temperature, and the resultant mixture was stirred under a nitrogen atmosphere at 110 to 115° C. for 19 hours. The reaction mixture was cooled to room temperature, then water and ethyl acetate were added to the reaction mixture, the resultant mixture was filtrated using Celite, and a filtrate was partitioned between aqueous layer and organic layer. The aqueous layer was extracted with ethyl acetate. The combined organic layers were filtrated using a glass filter having silica gel laid thereon. The silica gel was washed with ethyl acetate, organic layers obtained were combined, and the solvent was evaporated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (heptane:ethyl acetate=7:1 and then 4:1) to give the title compound (195 g, yield: 89%).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([OH:19])(=[O:18])[CH:16]=O.[CH3:20][O:21][C:22]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][C:23]=1[CH:24]=[CH2:25]>>[CH3:20][O:21][C:22]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][C:23]=1[CH:24]1[C:10]2[C:11](=[CH:13][CH:14]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[NH:12][CH:16]([C:15]([OH:19])=[O:18])[CH2:25]1
Reactant: O=CC(=O)O
Reactant: C=Cc1ccc(OC)c(C)c1OC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C2CC(C(=O)O)Nc3ccc(Oc4ccccc4)cc32)c(OC)c1C

Procedure:
Compound 75 was prepared from 4-phenoxyaniline, glyoxylic acid and 2,4-dimethoxy-3-methylstyrene by the automated process.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:24])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[F:23])[CH:13]=2)[NH:8][N:7]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O>[F:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[CH3:24])[NH:8][N:7]=[C:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1n[nH]c2cc(C)c(-c3ccc(OC)cc3F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2C)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylic acid ethyl ester (292 mg, 0.89 mmol) in THF (4 mL) was added a solution of LiOH (298.0 mg, 12.25 mmol) in water (2 mL). The reaction mixture was heated to reflux for 9 hours, and stirred at room temperature for an additional 48 hours. 1 N HCl solution was added to acidify the solution to pH 2. White solid formed, which was collected with filtration and dried in a vacuum oven at 50° C. for 4 hours to give the title compound (240 mg, 90% yield) as a solid. MS (ES+) 301.2 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.51 (s, 1H), 7.22 (dd, J=8.70, 8.70 Hz, 1H), 6.87 (dd, J=8.42, 2.56 Hz, 1H), 6.81 (dd, J=11.59, 2.56 Hz, 1H), 3.88 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>>[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:16]=1[C:21](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:18]2=[O:19]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(F)cccc21
Product: COC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.24 g, 28%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 3-fluorophthalic anhydride (0.57 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([O:29]C)=O)[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4].O.[NH2:39][NH2:40]>>[NH:1]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([NH:39][NH2:40])=[O:29])[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4]
Reactant: NN
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)NN
Reaction time: 2 h

Procedure:
17 g of Boc-Ser-Asn-Leu-Ser-OMe are dissolved in 200 ml of hydrazine hydrate, stirred for 2 hours at 20°, and evaporated to dryness at 25°. The residue is washed with diethylether, dried, and the title compound is obtained.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH:16](O)=[O:17]>>[CH2:1]([O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH:15][CH:16]=[O:17])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OC)c1nsc(N)n1
Reactant: O=CO
Product: CCON=C(C(=O)OC)c1nsc(NC=O)n1
Temperature: 75 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
Methyl 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (5.75 g, 25 mmol) in 99% formic acid (16.3 g) was heated under stirring at 75° C. for 6 hrs. The reaction mixture was treated in the same procedure as in Example 8 to give methyl 2-ethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (3.2 g, yield: 49.6%).