Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:26]Br>C(Cl)Cl>[C:1]([NH:8][C:9]1[S:10][C:11]([Br:26])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOP(=O)(COC(=O)c1csc(NC(=O)OC(C)(C)C)n1)OCC
Reactant: BrBr
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1Br)OCC

Procedure:
A solution of 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) in CH2Cl2 (5 mL) was treated with bromine (2 mmole) at room temperature for 4 h. Evaporation and extraction gave 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole as an orange oil which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-bromo-4-phosphonomethoxycarbonylthiazole (18.2) as a solid. Mp>230° C. (decomp). Anal. Calcd. for C5H6N2O5PSBr: C: 18.94; H: 1.91; N: 8.84. Found: C: 19.08; H: 1.76; N: 8.67.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C(O)CCC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][CH2:18][OH:19])([O-:14])=[O:13]
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCO
Reaction time: 8 h

Procedure:
A mixture of 100 parts of 1-chloro-2-nitro-4-(trifluoromethyl)benzene, 90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and heated till reflux. Stirring at reflux is continued overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and the whole is acidified with a hydrochloric acid solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The solid residue is crystallized from petroleumether. The product is filtered off and dried, yielding 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:18]([OH:20])=[O:19])[CH2:6][S:7][S:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:17])[CH3:16])[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:28](Br)[CH:29]=[CH2:30].[CH3:32][C:33]([CH3:35])=O>O>[CH2:28]([O:12][C:11](=[O:13])[C@H:10]([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][S:8][S:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([O:20][CH2:35][CH:33]=[CH2:32])=[O:19])[CH:29]=[CH2:30]
Reactant: CC(C)=O
Reactant: CC(=O)N[C@H](CSSC[C@@H](NC(C)=O)C(=O)O)C(=O)O
Reactant: C=CCBr
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@@H](CSSC[C@@H](NC(C)=O)C(=O)OCC=C)NC(C)=O

Procedure:
A solution of bis-N-acetyl D-cystine (3.2 g) in acetone (30 ml) containing triethylamine (4.0 g) is stirred with allyl bromide (4 ml) for 24 hours. The mixture is diluted with water, washed with 1N sodium hydroxide, 1N hydrochloric acid, brine, dried over sulfate and evaporated to afford bis N-acetyl-D-cystine bis allyl ester. Treatment of this bis compound according to the procedure of Preparation I affords the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:49]2[N:50]=[C:51]([NH2:53])[S:52][C:48]=2[C:47]([N:54]([CH3:62])[CH2:55][CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)=[CH:46][CH:45]=1>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:53][C:51]1[S:52][C:48]2[C:47]([N:54]([CH3:62])[CH2:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[CH:46][CH:45]=[C:44]([O:43][CH3:42])[C:49]=2[N:50]=1)=[O:7]
Reactant: COc1ccc(N(C)CC2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(N(C)CC2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 5 h
Yield: 14.4 %

Procedure:
To a stirred solution of 99 mg (0.49 mmol) 2-bromo-isonicotinic acid in 3 ml THF were added 195 mg (0.51 mmol) HATU and 0.11 ml (0.98 mmol) N-methylmorpholine and stirring continued at 30° C. for 5 h. 75 mg (0.24 mmol) 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-ylmethyl)-benzothiazole-2,7-diamine was then added and stirring continued at 40° C. for 16 h. The reaction mixture was then diluted with ethyl acetate and washed sequentially with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated in vactio. Flash chromatography (methanol/dichloromethane) followed by trituration in ether/hexane afforded 17 mg (14%) 2-bromo-N-{4-methoxy-7-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino)-benzothiazol-2-yl}-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 493 (M{81Br}+H+, 100), 491 (M{79Br}+H+, 95).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:15]=[CH:14][CH:13]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH:17]1([N:16]2[C:12]([NH:11][C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1ccnn1C1CCCC1
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Nc1ccnn1C1CCCC1
Temperature: 0 °C
Yield: 68.5 %

Procedure:
A mixture of 2-iodobenzoic acid (28 g, 0.113 mol), 5-amino-1-cyclopentylpyrazole (17 g, 0.113 mol), DMF (100 ml), potassium carbonate (16 g, 0.113 mol) and Cu(OAc) 2 (0.5 g) was refluxed overnight. The reaction mixture was poured into ice-water, and acidified with acetic acid to a pH of 5. The gum which formed was extracted with CH2Cl2 and the CH2Cl2 layer was washed with water, dried over MgSO4, and evaporated to afford 21 g of N-(1-cyclopentyl pyrazol-5-yl) anthranilic acid.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.Cl.[N:13]1([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:8][N:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]([N:16]2[CH2:17][CH2:18][N:13]([C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])[CH2:14][CH2:15]2)=[N:7]1.[C:21]1([CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: Cl
Product: Cc1ccccc1
Product: Cn1nc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Yield: 55 %

Procedure:
The compound 5 (solid) is prepared from the triazine 1b and the intermediate 6a according to the synthesis method 1 in toluene (yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:16]#[CH:17])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:18]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C=O.[C:26](O)(=O)C>[Cu]Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:12]([F:13])([F:14])[F:15])([C:16]#[C:17][CH2:26][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:6]=2[CH:18]=1
Reactant: CC(=O)O
Reactant: C1CCNC1
Reactant: C#CC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Agent: Cl[Cu]
Agent: C=O
Solvent: C1COCCO1
Product: O=C1Nc2ccc(Cl)cc2C(C#CCN2CCCC2)(C(F)(F)F)O1
Yield: 71.7 %

Procedure:
A dioxane solution of (+/-) 6-chloro-4-ethynyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (150 mg, 0.544 mmol), pyrrolidine (52.2 gL, 0.626 mmol), paraformaldehyde (20.5 mg, 0.681 mmol), acetic acid (31.1 gL, 0.544 mmol) and copper (I) chloride (20.5 mg, 0.207 mmol in 3.5 ml dioxane) was heated to 50° C. in an oil bath for approximately 2 h. The reaction mixture was quenched into 2N HCl and extracted with ethyl acetate. The aqueous layer was neutralized with solid potassium carbonate and extracted with ethyl acetate (3x). The combined extracts were washed with water and brine before drying over sodium sulfate to afford 140 mg crude product. Chromatographic purification on silica gel and recrystallization from ethyl acetate: hexane afforded crystalline (+/-) 6-chloro-4-(1,1,1-trifluoromethyl)-4-[(3-(1-pyrrolidinyl))-1-propynyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one (89 mg, 46% yield): MP 160°-161° C. (dec). 1H-NMR (CDCl3): δ1.85-1.89 (m, 4H), 2.68-2.71 (m, 4H), 3.67 (s, 1H), 6.88 (d, J=8.55 Hz, 1H), 7.40 (dd, J=2.19, 8.54 Hz, 1H), 7.55 (s, 1H), 9.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:18])=[C:4]([F:19])[CH:3]=1.[Li+].[OH-]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:18])=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1cncc(F)c1-c1ccc(Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc(F)c1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To the solution of methyl 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinate (600 mg, 2.115 mmol) in tetrahydrofuran (2.5 mL), MeOH (2.5 mL) and water (2.5 mL) was added LiOH (50.7 mg, 2.115 mmol) and the mixture was stirred at rt for 12 h. The volatiles were removed and the residue was diluted with water. The pH was adjusted to 4 with 1.5N HCl. The product was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinic acid (530 mg, 1.966 mmol, 93% crude yield) the pale brown solid. The material was carried on without further purification. LC/MS (ESI) m/e 269.9 [(M+H)+, calcd for C12H7ClF2NO2 270.0]; LC/MS retention time (method D): tR=0.88 min.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)=O.CN(C)CCN>C1COCC1>[CH3:27][N:29]([CH3:30])[CH2:33][CH2:32][NH:31][C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)=[O:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 86.2 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared as described in example 1. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.8 g, 2.19 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.). The resulting acyl imidazole was then treated with N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq). When complete, the reaction was worked up and the resulting yellow oil purified as described in example 3 to give 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide (0.82 g, 86% yield) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[CH2:12]1[O:23][C:22]2[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][C:14]=2[O:13]1>>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:22]3[O:23][CH2:12][O:13][C:14]=3[CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C=C(N)OCC
Product: Nc1cc(=O)n(Cc2ccc3c(c2)OCO3)[nH]1

Procedure:
From 17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 16.6 g of 3,4-methylenedioxybenzylhydrazine, analogously to the procedure described in Example 1. 12.1 g of the compound identified above, as colorless crystals of melting point 218°, corresponding to 52% of theory, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH3:11])[CH:3]=1.[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:29][C:26]2[CH:25]=[CH:24][C:23]([C@H:22]3[C:15]4=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]4[CH2:19][CH2:20][CH2:21]3)=[CH:28][CH:27]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc(Cl)ccc1Oc1ccc([C@@H]2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
A mixture of (4-chloro-2-methylphenyl)boronic acid (912 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL) cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (5.00 g) in MeCN (18 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (37.0 mg) as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C([O-])(=O)C.[Na+].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.[OH-].[Na+]>>[C:14]([O:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:15])[CH2:13][C:12]([CH3:11])=[O:16]
Reactant: C=C1CC(=O)O1
Reactant: OCCCBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC(=O)OCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
90 g of 3-bromopropanol was added to 8 g of sodium acetate, to which 59.8 g of diketene was added dropwise controlling the reaction mixture at 40°-50° C. The mixture was further stirred at room temperature for 3 hours. The reaciton mixture was poured into ice water containing a diluted aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane and the dichloromethane layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 102.6 g of 3-bromopropyl acetoacetate.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)#[N:24]>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=3)=[O:33])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: N#Cc1ccc(N=C=O)cc1
Product: N#Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Yield: 53 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-cyanophenyl isocyanate in a yield of 53%, according to the procedure for the synthesis of example 42.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(OC(Cl)=O)C(C)C.CN1CCOCC1.Cl.[CH3:46][C:47]([CH3:51])([OH:50])[CH2:48][NH2:49]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([NH:49][CH2:48][C:47]([OH:50])([CH3:51])[CH3:46])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(C)(O)CN
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)O)cn1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)NCC(C)(C)O)cn1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.42 g, 0.9 mmol) in DMF (3.0 mL) was added isobutylchloroformate (0.126 g, 0.13 mmol) followed by the addition of N-methylmorpholine (0.11 g, 1.1 mmol) and stirred at −10° C., under argon atmosphere. After 20 min, added a solution of 1,1 dimethyl-2-aminoethanol hydrochloride (0.135 g, 1.1 mmol) in DMF (2.0 mL) containing N-methylmorpholine (0.11 g, 1.1 mmol). The mixture was stirred at room temperature for 1 h, and concentrated to dryness in vacuo. The resulting residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=537 M+H were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.35 g, 75%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 9.1 (d, 1H, J=1.6 Hz), 8.71 (d, 1H, J=1.6 Hz), 7.61 (m 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2 h). 3.30 (s, 2 h), 2.55 (s, 3H), and 1.21 (s, 6H); 19F NMR (CD3OD/400 MHz) −111.67 (m) and −116.05 (m); ES-HRMS m/z 537.0948 (M+H calcd for C23H24BrF2N4O4 requires 537.0943).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[N:13]3)[CH:8]=2)[CH2:3]1.C1CCN2C(=NCCC2)CC1.[CH3:37][CH:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:37][CH:38]([S:40]([NH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[C:16]([C:17]([F:18])([F:19])[F:20])=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[N:13]3)[CH:8]=2)[CH2:3]1)(=[O:42])=[O:41])[CH3:39]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](N)C3)c1C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-Ethyl 1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.102 mmol, 36 mg) was suspended in DCM (2 mL) and DBU (0.306 mmol, 0.046 mL, 46.5 mg) added which caused all solids to go into solution. Propane-2-sulfonyl chloride (0.204 mmol, 0.023 mL, 29.1 mg) was added dropwise and the reaction stirred at room temperature for 1 h. An additional 1 eq of sulfonyl chloride was added and the mixture stirred for a further 3 h before leaving to stand overnight and after this time an additional 2 eq. sulfonyl chloride and 3 eq. DBU added. The mixture was concentrated and purified on reverse phase HPLC to give the desired compound as a clear film (12 mg, 0.026 mmol, 25.6%). 1H NMR (400 MHz, CDCl3) δ 1.36 (m, 9H) 2.85 (m, 2H) 3.15 (m, 1H) 3.30 (m, 2H) 4.20 (m, 1H) 4.31 (m, 3H) 5.49 (s, 1H) 7.02 (m, 2H) 7.20 (d, 1H) 7.99 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]1([C:24](=[O:25])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])[CH2:22][CH2:23]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(=O)c2ccc(Br)cc2)CC1
Reaction time: 18 h
Yield: 89.6 %

Procedure:
2-Amino-1-(4-bromo-phenyl)-ethanone HCl (2.5 g, 10 mmol) in DMF (30 mL) was treated with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (1.97 g, 9.8 mmol), HATU (4.02 g, 10.5 mmol), and DIPEA (5.6 mL, 31.1 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (310 mL), H2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 and subjected to a 80 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford {1-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (3.49 g, 90%). This material (3.49 g, 8.8 mmol) in xylenes (20 mL) was treated with ammonium acetate (3.4 g, 44 mmol). The reaction was stirred at 130° C. in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO3 (50 mL). The solution was dried over MgSO4 to afford crude {1-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 379 [M+H]+.
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29]C(OC(C)(C)C)=O)[CH2:25]3)=[N:19][CH:20]=[C:21](Br)[CH:22]=2)(=[O:16])=[O:15])[CH2:10]1)C(=O)[O-])(C)C.[CH3:37][C:38]1([CH3:62])[CH2:47][CH2:46][C:45]2[N:44]=[CH:43][N:42]=[C:41]([N:48]3[CH2:54][C:53]4[CH:55]=[C:56](B(O)O)[CH:57]=[CH:58][C:52]=4[O:51][CH2:50][CH2:49]3)[C:40]=2[CH2:39]1>>[NH2:29][C@H:26]1[CH2:27][CH2:28][N:24]([C:18]2[C:17]([S:14]([N:11]3[CH2:12][CH2:13][C@H:9]([NH2:5])[CH2:10]3)(=[O:16])=[O:15])=[CH:22][C:21]([C:56]3[CH:57]=[CH:58][C:52]4[O:51][CH2:50][CH2:49][N:48]([C:41]5[C:40]6[CH2:39][C:38]([CH3:37])([CH3:62])[CH2:47][CH2:46][C:45]=6[N:44]=[CH:43][N:42]=5)[CH2:54][C:53]=4[CH:55]=3)=[CH:20][N:19]=2)[CH2:25]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(Br)cc2S(=O)(=O)N2CC[C@H](N(C(=O)[O-])C(C)(C)C)C2)C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N6CC[C@H](N)C6)c(S(=O)(=O)N6CC[C@H](N)C6)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 1,1-dimethylethyl[(3S)-1-({5-bromo-2-[(3S)-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)pyrrolidin-1-yl]pyridin-3-yl}sulfonyl)pyrrolidin-3-yl]carbamate (reagent preparation 40) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.56 (s, 1H), 8.55 (s, 1H), 8.53 (s, 1H), 7.74 (s, 1H), 7.52 (d, 1H), 7.01 (d, 1H), 5.12 (s, 2H), 4.47 (m, 2H), 4.32 (m, 3H), 4.22 (m, 1H), 4.05 (m, 2H), 3.85 (m, 1H), 3.74 to 3.56 (m, 5H), 2.85 (t, 2H), 2.59 (s, 2H), 2.35 (m, 2H), 2.22 (m, 2H), 1.70 (t, 2H), 0.93 (s, 6H); MS (EI) for C32H42N8O3S: 619 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1Cl)=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:23])=[N:19][C:20]=1[O:21][CH3:22]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:23][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[C:20]([O:21][CH3:22])[N:19]=1)=[O:4]
Reactant: COc1ccc(N)nc1OC
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1ccc(OC)c(OC)n1
Temperature: 70 °C
Yield: 52.9 %

Procedure:
A mixture of 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (1.0 g, 4.83 mmol) and 5,6-dimethoxypyridin-2-amine (968 mg, 6.28 mmol) was dissolved in acetonitrile (5 mL) and heated at 70° C. for 16 h. The mixture was concentrated in vacuo and the crude mass obtained was purified by chromatography (silica, 100-200 mesh, 10-70% ethyl acetate in hexane) to give 6-chloro-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid methyl ester (830 mg, 53%) as a yellow solid. LC-MS: 325.2 [M+H]+.