Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][N:19]([CH3:27])[C:15]=3[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3nc[nH]c3c2)c(SC)s1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3ncn(C)c3c2)c(SC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (as prepared in Example 38, step e) (100 mg, 0.22 mmol) in dimethylformamide (2 mL) was added MeI (13.9 μL, 0.22 mmol) and K2CO3 (61.8 mg, 0.45 mmol), then stirred overnight at room temperature. The solvents were removed in vacuo and the residue was diluted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (15 mL) and brine (25 mL), and dried over MgSO4. The solvent was removed in vacuo to afford 20 mg (19%) of 4-(7-bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(7-bromo-1-methyl-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a mixture. This mixture was used directly in the following step.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(CC)CC>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), CuI (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrorolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[O:18][C@@H:17]([N:45]2[CH:52]=[CH:51][C:49](=O)[NH:48][C:46]2=[O:47])[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:65])([F:64])[F:63])[C:58]([F:61])([F:60])[F:59])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2].[C:66]([NH:69]C1C=CN([C@@H]2O[C@H](COC(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[C@@H](O)[C@H]2OCOCC(C(F)(F)F)C(F)(F)F)C(=O)N=1)(=[O:68])[CH3:67]>>[C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[O:18][C@@H:17]([N:45]2[CH:52]=[CH:51][C:49]([NH:69][C:66](=[O:68])[CH3:67])=[N:48][C:46]2=[O:47])[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:64])([F:65])[F:63])[C:58]([F:61])([F:60])[F:59])([N:7]([CH:8]([CH3:10])[CH3:9])[CH:11]([CH3:13])[CH3:12])[OH:6])#[N:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 86 %

Procedure:
This compound was synthesized in the same manner as that used for the compound 3u by using the compound 2c instead of the compound 2u. Yield was 86% (white foam).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([OH:35])[CH2:34][NH:33][CH2:32]3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:45]([N:33]1[CH2:34][C:31]([C:28]2[CH:29]=[CH:30][C:25]([N:9]3[C:10](=[O:24])[CH2:11][C:12]4[C:17](=[CH:16][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=4)[C@@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][CH:27]=2)([OH:35])[CH2:32]1)(=[O:47])[CH3:46]
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CNC3)cc1)C(=O)C2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CN(C(C)=O)C3)cc1)C(=O)C2
Temperature: 0 °C

Procedure:
A solution of (S)-1-(4-chloro-phenyl)-2-[4-(3-hydroxy-azetidin-3-yl)-phenyl]-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one (example 56) (40 mg, 0.081 mmol) in DCM (2 ml) was immersed in an ice-bath. DIPEA (Fluka) (0.043 ml, 0.243 mmol) was added, followed by acetyl chloride (Aldrich) (7.50 μl, 0.105 mmol). Afterwards the reaction was stirred in the ice-bath for 30 min. The reaction mixture was taken up in aqueous NaHCO3 solution. The organic phase was extracted two times with DCM. The organic layers were pooled, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative TLC (DCM/MeOH 9:1; Rf range from 0.08 to 0.15 was scratched from the plate). The silicagel was taken up in 20 ml DCM/MeOH 1:1. The silicagel was filtered off and the filtrate was evaporated in vacuo to obtain the title compound as yellowish solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[C:11]([CH3:15])=[N:12][N:13]([CH3:14])[C:9]=2[C:8](=[O:16])[NH:7][C:6]2[N:17]=[CH:18][CH:19]=[CH:20][C:5]1=2)=[O:3].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22]>C(#N)C>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[C:11]([CH3:15])=[N:12][N:13]([CH3:14])[C:9]=2[C:8](=[O:16])[NH:7][C:6]2[N:17]=[CH:18][CH:19]=[CH:20][C:5]1=2)=[O:3])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: Cc1nn(C)c2c1N(C(=O)Cl)c1cccnc1NC2=O
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2cccnc2NC(=O)c2c1c(C)nn2C
Yield: 17 %

Procedure:
Prepared analogously to Example 2 from 4-(chlorocarbonyl)-1,3-dimethyl-1,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[2,3-b][1,4]diazepin-10-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 17% of theory. Colourless crystals, m.p. 138°-139° C. (acetonitrile).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[K].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([N+]([O-])=O)[CH:9]=1.O>CN(C)C=O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:9]=1
Reactant: CC(C)=NO
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(Cl)ccc1C#N
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
In 75 ml of dry N,N-dimethylformamide was dissolved acetone oxime (1.21 g), followed by potassium tertiaryl butoxide (1.85 g) and stirred under nitrogen. After 30 minutes, 4-chloro-2-nitro-benzonitrile (2.00 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of the product, m.p. 83°-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]([O:26]CC)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[NH3:29].CO>>[NH2:29][C:24](=[O:26])[CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: N
Reactant: CCOC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC(N)=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)-piperidine-1-carboxylate (0.971 g, 2.36 mmol) was dissolved in 7 M NH3/MeOH (20 mL), and stirred overnight at room temperature. The solvent was removed under reduced pressure to give (R)-tert-butyl 3-((R)-(2-amino-2-oxoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (902 mg, 100%), which was used for the next step without further purification. MS ESI+ve m/z 383 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cncc(Br)c2)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cncc(COCC2(c3ccccc3)CCNCC2)c1
Reaction time: 1 h
Yield: 112.4 %

Procedure:
A solution of tert-butyl 4-(((5-bromopryidin-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.2 mmoL) in methylene chloride (2 mL) was treated with TFA (0.5 mL). After 1 h, the reaction was concentrated, and the resulting residue was evaporated from methylene chloride (2×). Preparative HPLC afforded 88.0 mg (92%) of the desired compound as its TFA salt. 1H-NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.52 (s, 1H), 7.84 (s, 1H), 7.24-7.43 (m, 5H), 6.85 (s, br, 1H), 4.46 (s, 2H), 3.45 (s, 2H), 3.33-3.38 (m, 2H), 2.91-2.95 (m, 2H), 2.43-2.48 (m, 2H), 2.22-2.30 (m, 2H). Mass spec.: 362.99 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])#[N:20]
Reactant: CC(C)(C)CC(C)(N)C#N
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Product: CC(C)(C)CC(C)(C#N)NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 78d) and 2-amino-2,4,4-trimethylpentanenitrile (CAN 65260-84-6) as starting materials and isolated (643 mg, 87%) as a yellow oil; MS (ESI, m/z): 422.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:17][NH:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:18]([CH3:19])[CH3:17])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1n[nH]c2cc(Br)ccc12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)Cc1n[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1H-indazole-3-carbaldehyde (300 mg, 1.33 mmol) in THF (1 mL) was added acetic acid (0.11 mL, 2 mmol), 2M dimethylamine in THF (1.33 mL, 2.66 mmol) and sodium triacetoxyborohydride (283 mg, 1.33 mmol). The reaction was stirred at RT for 2 hr then allowed to stand at RT for 18 hr. The mixture was concentrated in vacuo, then diluted with EtOAc (50 mL) and washed with 1M aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5 mL), followed by water (5 mL). The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a beige solid: 1H NMR (500 MHz, MeOD) δ 2.31 (6H, s), 3.85 (2H, s), 7.27 (1H, dd, J=8.67, 1.58 Hz), 7.68-7.72 (1H, m), 7.77 (1H, d, J=8.67 Hz). LC-MS: m/z=+253.9/255.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:11])[CH:5]=1.[C:13](Cl)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[C:6]([I:11])[CH:5]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(I)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(C)=O)c(I)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-amino-3-iodo-benzoic acid methyl ester (11.1 g, 40.0 mmol) in pyridine (80 mL) was added acetyl chloride (3.30 g, 42.0 mmol) at 0° C. under nitrogen. Stirring continued at 0° C. for 30 minutes. The ice-bath was removed, and stirring continued at room temperature for 16 hours. Pyridine was evaporated under reduced pressure. The residue was taken in ethyl acetate (300 mL). The organic phase was washed with 2 N aqueous HCl (200 mL), water (200 mL), brine (200 mL), and then dried over anhydrous Na2SO4. Removal of solvent gave 4-acetylamino-3-iodo-benzoic acid methyl ester as a white solid. Yield: 12.71 g (99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1.CS(C)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1NC1CC1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoic acid ethyl ester (Example 2c, 9.34 g, 23.1 mmol), cyclopropylamine (16 mL, 228 mmol), and dimethyl sulfoxide (30 mL) is heated in a sealed tube at 110° C. for 3 days. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford a brown residue. The residue is then purified via flash column chromatography (1:1 ethyl acetate/hexanes) to afford the title compound (4.41 g). MS CI: m/z 442 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: OCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-aminoethanol according to general procedure 1 providing the intermediate (78 mg, 32%) as a white solid: Rf=0.41 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.73 (d, J=9.7 Hz, 1H), 3.80 (t, J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H); ES-MS: (M+H)=257, 259 m/z.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13]C)=[CH:4][C:5]([O:11]C)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.C[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30]C)[CH:24]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[F:29][C:26]1[C:25]([OH:30])=[CH:24][C:23]([OH:22])=[C:28]([CH:27]=1)[C:7]([C:6]1[CH:10]=[C:2]([F:1])[C:3]([OH:13])=[CH:4][C:5]=1[OH:11])=[O:9]
Reactant: COc1cc(OC)c(C(=O)O)cc1F
Reactant: COc1ccc(F)c(OC)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cc(F)c(O)cc1O)c1cc(F)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
2,4-dimethoxy-5-fluorobenzoic acid 6 (5.4 g, 27 mmol) in dry CH2Cl2 (100 mL) was treated with 10.6 mL of oxalyl chloride under an Ar atmosphere and stirred at room temperature overnight. The excess reagent and solvent were removed under reduced pressure. The residue, 2,4-dimethoxy-5-fluorobenzoyl chloride, was redissolved in anhydrous CH2Cl2 (125 mL). 1,3-dimethoxy-4-fluorobenzene 3 (3.29 mL, 26 mmol) and AlCl3 (10.8 g, 81 mmol) were added at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was allowed to warm to room temperature for 67 h, the mixture was then hydrolyzed with 1M HCl (300 mL) at 0° C. and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 30%-40% EtOAc in hexane to yield 7 (3.3 g, 44%) as a yellow solid. 1H NMR (300 MHz, MeOH-d4) 7.14 (d, 2H, J=11.5 Hz), 6.46 (d, 2H, J=7.4 Hz); 13C NMR (75 MHz, MeOH-d4) δ 199.1, 159.0, 152.9, 152.7, 147.7, 144.5, 119.2, 118.9, 114.2, 114.1, 106.1, 106.0; 19F NMR (282 MHz, MeOH-d4). δ −149.8 (dd, 2F).
Reaction SMILES: [CH2:1]([C:15]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:18]([NH2:19])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=1)[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O>C(O)C.C(O)=O>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[N:19][C:18]1[C:20]([CH:22]([CH3:24])[CH3:23])=[CH:21][C:15]([CH2:1][C:2]2[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([N:6]=[CH:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=2)=[CH:16][C:17]=1[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(Cc2cc(C(C)C)c(N)c(C(C)C)c2)cc(C(C)C)c1N
Reactant: O=Cc1ccccn1
Solvent: O=CO
Solvent: CCO
Product: CC(C)c1cc(Cc2cc(C(C)C)c(N=Cc3ccccn3)c(C(C)C)c2)cc(C(C)C)c1N=Cc1ccccn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a suspension of 2b (1.60 g, 4.37 mmol) in absolute ethanol (10 ml) was added 2-pyridinecarboxaldehyde (1.24 ml, 13.11 mmol, 3 eq.) and two drops of formic acid. The mixture was stirred at 45° C. overnight. On cooling to room temperature the suspension was filtered, washed with cold ethanol and dried under reduced pressure to afford 18a as a yellow solid (1.68 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[O:34])=[CH:3][CH:4]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N2-(4-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.022 g, 0.07 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)phenyl isocyanate (0.030 mL, 0.2 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm to room temperature and left stirring for 1 hour. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD75. ESI-MS m/z[M+H]+. Found 495.5. Calculated 495.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N+:6]=1[O-])(=[O:3])[CH3:2].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][C:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc(C)c[n+]1[O-]
Product: CC(=O)Nc1ccc(C)c(OC(C)=O)n1
Temperature: 25 °C

Procedure:
A solution of 2-acetamido-5-methylpyridine N-oxide (28.2 g, 170 mmol) in acetic anhydride (840 mL) was stirred at 70° C. for 4 h. After cooling to rt and concentration in vacuo Et2O (180 mL) was added and the resulting solids isolated by filtration and washed with MeOH to give 6-acetamido-3-methylpyridin-2-yl acetate (6.87 g, 33.0 mmol) as a pale brown solid.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([Cl:32])=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[CH:23]=2)[O:7][C@@H:6]1[CH2:33][O:34]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:32][C:21]1[S:20][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:33][OH:34])[O:7]2)=[CH:23][C:22]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C)cc3)c(Cl)s2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.4 %

Procedure:
To a suspension of acetate 40 (339 mg, 0.612 mmol) in MeOH (15 mL) was added NaOMe (25 wt % in MeOH, 0.2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 41 (55 mg, 23%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C@H:8]3[CH2:9][CH2:10][C@H:11]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[NH:16][C:15]4=[O:23])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)=[O:39])[CH:34]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of 0.050 g of 1,3-dihydro-1-{trans-4-[4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one and 0.023 mL of triethylamine in 1.5mL of dichloromethane was added 0.024 g of nicotinoyl chloride hydrochloride. After 12 h, 20 mL of saturated sodium carbonate was added, the organic layer was separated, and the aqueous layer extracted with two addtional 20 mL portions of chloroform. The combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol/10% conc. NH4OH in chloroform gave 0.024 g of 1,3-dihydro-1-{trans -4-[1-(3-pyridinecarbonyl)-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.04 (s, 1H), 8.68 (dd, 2H), 7.77 (m, 1H), 7.38 (m, 1H), 7.26 (m, 1H), 7.06 (m, 3H), 4.67 (br s, 1H), 3.75 (br s, 1H), 3.18 (br s, 2H), 2.99 (br s, 1H), 2.87 (br s, 1H), 2.55 (q, 2H), 2.13-1.9 (m, 4 H), 1.72-1.3 (m, 7H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C24H29N5O2.2HCl.0.90 CHCl3.0.25 CH3CO2CH2CH3C: 50.02, H: 5.95, N: 11.26 found C: 51.28, H: 5.49, N: 11.53.