Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]([CH3:17])[C:6](=[O:16])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:9].Cl.NCC(OC)=O.OC1C2SC=CC=2N(C)C(=O)C=1C(OCC)=O>O1CCOCC1>[OH:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]([CH3:17])[C:6](=[O:16])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: COC(=O)CNC(=O)c1c(O)c2sccc2n(C)c1=O
Agent: CCOC(=O)c1c(O)c2sccc2n(C)c1=O
Agent: COC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2sccc21
Temperature: 100 °C
Reaction time: 15 h

Procedure:
Methyl 2-(7-hydroxy-4-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamido)acetate. A mixture of methyl 2-aminoacetate hydrochloride (291 mg, 2317 μmol) and ethyl 7-hydroxy-4-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxylate (489 mg, 1931 μmol) in 15 mL dioxane was heated to 100° C. in a sealed tube and stirred for 15 hours. The mixture was cooled to room temperature, and the resulting suspension was added dropwise to 100 mL ice-water. The precipitate was collected by filtration, washed with H2O, and dried in vacuo. The solids were triturated with Et2O, collected by filtration, and dried to give a beige solid. Purification of the crude product by flash chromatography (Gradient from hexanes to hexanes/EtOAc=1:1) gave the title compound as a white solid (301 mg). MS (ESI) m/z: Calculated; 296.3: Observed; 297.1. 1H NMR (300 MHz, CDCl3) δ ppm 10.73 (1H, br. s), 7.78 (1H, d, J=5.3 Hz), 7.08 (1H, d, J=5.3 Hz), 4.24 (2H, br. s), 3.79 (3H, s), 3.69 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[S:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](=[O:29])[CH2:27]Br)=[CH:25][C:20]=2[N:19]=[N:18]1>>[S:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](=[O:29])[CH2:27][N:12]3[C:4]4=[N:3][C:2]([Cl:1])=[CH:7][C:6](=[O:8])[N:5]4[CH2:9][CH2:10][C@H:11]3[C:13]([F:14])([F:15])[F:16])=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(CBr)c1ccc2snnc2c1
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc2snnc2c1

Procedure:
150 mg (0.59 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 167.25 mg (0.65 mmol) of 1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone were used in the reaction. After purification by chromatography on silica gel (eluent: 90/10 DCM/MeOH), 210 mg of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[N:13]([CH3:14])[CH:12]=[C:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]Br>C(Cl)Cl>[CH3:2][C:1]([CH3:4])([S@@:5]([NH:7][C@@H:8]([C:9]1[N:13]([CH3:14])[CH:12]=[C:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:10]=1)[CH3:22])=[O:6])[CH3:3]
Reactant: Cn1cc(C(=O)OC(C)(C)C)cc1/C=N/[S@@](=O)C(C)(C)C
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(C(=O)OC(C)(C)C)cn1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)-1-methyl-1H-pyrrole-3-carboxylate (3.0 g, 10 mmol) in DCM (60 mL) was slowly added methylmagnesium bromide (13.3 mL, 3.0 M in ether) at −78° C. After stirring at −78° C. for 1 h, the solution was warmed to rt and stirred for 2 h. The reaction was quenched with sat. NH4Cl solution. After separation, the organic phase was washed with brine (5 mL), dried (Na2SO4) and concentrated. Flash column chromatography (petroleum ether: EtOAc, 10:1 to 1:1) afforded tert-butyl 5-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1-methyl-1H-pyrrole-3-carboxylate (2.2 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 7.15 (s, 1H), 6.47 (s, 1H), 4.48 (m, 1H), 3.62 (s, 3H), 3.18 (m, 1H), 1.68 (d, J=6.6 Hz, 3H), 1.52 (s, 9H), 1.19 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]1[N:16]2[C@@H:10]([S:11][CH2:12][CH2:13][C@H:14]([NH:18]C(=O)OC(C)(C)C)[C:15]2=[O:17])[CH2:9][CH2:8][CH2:7]1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:18][C@H:14]1[CH2:13][CH2:12][S:11][C@H:10]2[CH2:9][CH2:8][CH2:7][C@@H:6]([C:2]3[O:1][CH:5]=[N:4][N:3]=3)[N:16]2[C:15]1=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (4S,7S,10aS)-7-(1,3,4-oxadiazol-2-yl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (22 mg, 0.060 mmol) in DCM (0.6 mL) at 0° C., was added TFA (0.323 mL, 4.20 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was concentrated to give (4S,7S,10aS)-4-amino-7-(1,3,4-oxadiazol-2-yl)hexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5 (7H)-one 2,2,2-trifluoroacetate (23 mg, 0.060 mmol, 100% yield). Anal. Calcd. for C11H16N4O2S m/z 268.4. found: 269.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:6][C:7]([C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14](=[O:34])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=C)=[O:27])=[O:20])=[O:8])[CH2:2][CH2:3][CH:4]=C>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[N:10]12[CH2:11][CH2:12][CH2:13][C@@H:9]1[C:7](=[O:8])[O:6][CH2:1][CH2:2][CH2:3][CH:4]=[CH:32][CH2:31][CH2:30][CH2:29][O:28][C:26](=[O:27])[C@@H:22]1[N:21]([CH2:25][CH2:24][CH2:23]1)[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:34]
Reactant: C=CCCCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCCCC=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: O=C1OCCCC=CCCCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Temperature: 50 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A mixture of 1.20 g (2.5 mmol) (R)-1-[6-[(R)-2-pent-4-enyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid pent-4-enyl ester and 40 mg benzylidene-bis(tricyclohexylphosphine)dichlororuthenium in 30 ml dry dichloromethane was stirred at 50° C. overnight. Removal of the solvent and chromatography on silicagel with ethylacetate/acetone with a ratio of 8/2 gave 430 mg (38%) (12R,25R)-14,23-dioxa-1,8-diaza-tricyclo[23.3.0.0 8,12]octacos-18-ene-2,7,13,24-tetraone as an oil, MS m/e (%): 449 (M+H+, 100).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:10][CH3:11])=[N:6][O:7][C:8]=1[CH3:9])(=O)[CH3:2].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[C:12]1([NH:18][N:19]=[C:1]([C:4]2[C:5]([CH2:10][CH3:11])=[N:6][O:7][C:8]=2[CH3:9])[CH3:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1noc(C)c1C(C)=O
Reactant: NNc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: CCc1noc(C)c1C(C)=NNc1ccccc1

Procedure:
A mixture of 61.1 g. (0.4 mole) of 4-acetyl-3-ethyl-5-methyl-isoxazole, 39.4 ml. (0.4 mole) of phenyl hydrazine and 500 mg. toluenesulfonic acid in 400 ml. ethanol is stirred at room temperature for 48 hours. The resulting solid is filtered and washed with cold ether to give 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethanone phenyl hydrazone; m.p. 72° to 75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-{4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (29 mg, 25%).
Reaction SMILES: C([O:3][C:4](=[O:51])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:25]=[C:24]([C:34]3[CH:43]=[CH:42][C:37]4[O:38][CH2:39][CH2:40][O:41][C:36]=4[CH:35]=3)[CH:23]=2)[C:10]=1[CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])C.[OH-].[Na+]>>[C:46]([CH2:45][CH2:44][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:25]=[C:24]([C:34]3[CH:43]=[CH:42][C:37]4[O:38][CH2:39][CH2:40][O:41][C:36]=4[CH:35]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:51])=[O:3])([OH:48])=[O:47]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)O
Yield: 86 %

Procedure:
A similar procedure as described in Example 22, step 3 was used, starting from 4-[3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-4-yl-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (75 mg, 0.1 mmol) and 1.0 N aqueous sodium hydroxide (6 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-4-yl-phenoxy]-hexyl}-phenoxy)-butyric acid (55 mg, 86%) as an amorphous off-white solid: ES(+)-HRMS m/e calculated for C38H41NO8 (M+H)+ 640.2905, found 640.2899.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38]>>[CH3:38][CH:37]([CH3:39])[C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:40]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)C(C)C)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available isobutyryl chloride (Aldrich) via the parallel synthesis described above. MS-base peak at m/z=548 by positive ion CI.
Reaction SMILES: C(OC([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:20]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:21])[CH2:13]3)[CH:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH:10]1[C:11]2=[C:12]3[C:16](=[CH:17][CH:18]=[C:19]2[NH:8][CH:9]=1)[NH:15][CH:14]([C:20]([O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:21])[CH2:13]3
Reactant: CC(C)(C)OC(=O)n1ccc2c3c(ccc21)NC(C(=O)OCCc1ccc([N+](=O)[O-])cc1)C3
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCc1ccc([N+](=O)[O-])cc1)C1Cc2c(ccc3[nH]ccc23)N1

Procedure:
Two grams (4.43 mmol) of 14 are weighed into a round bottomed flask. Then, in a fume hood, 25 mL (325 mmol) of trifluroacetic acid is added, and the flask is capped and stirred. The solid dissolves in about a minute. The mixture is stirred for 1 hour, at which time deprotection will be done (HPLC can be used as a check). The acid is evaporated on a rotary evaporator (use a trap) and the product is dissolved in 100 mL of methylene chloride. This is extracted twice with 100 mL of half to 2/3 saturated sodium bicarbonate solution. The aqueous layers are back-extracted once with ˜50 mL of methylene chloride and this is combined with the rest. The organic layer is dried over sodium sulfate twice and evaporated to give a brown solid. If desired, this material can be recrystallized by diluting a very concentrated solution in methylene chloride with methanol and cooling. Yields approaching 100% are usually obtained. mp 192-194° C. 1H NMR (DMSO-d6) δ 11.51 (s, 1H), 8.18 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 1H), 6.80 (s, 1H), 6.70 (d, J=8.5 Hz), 5.03 (br s, 1H), 4.54 (t, J=6.4 Hz, 2H), 3.46 (t, J=8.6 Hz, 2H), 3.19 (m, 2H), 3.04 (t, J=8.6 Hz, 2H). Combustion Analysis: Calculated for C19H17N3O4: C, 64.94%; H, 4.88%; N, 11.96%. Found: C, 65.50%; H, 4.70%; N, 11.64%
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH2:12]O)=[CH:10][CH:9]=[CH:8][N:7]=1.CCN(C(C)C)C(C)C.S(Cl)(C)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]#[CH:38])=[CH:31][C:30]=1[C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[CH:43][CH:42]=1)=[O:40]>O1CCOCC1>[CH:47]([C:44]1[CH:43]=[CH:42][C:41]([C:39]([C:30]2[CH:31]=[C:32]([O:35][CH2:36][C:37]#[CH:38])[CH:33]=[CH:34][C:29]=2[NH:28][CH2:12][C:11]2[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=2)=[O:40])=[CH:46][CH:45]=1)([CH3:49])[CH3:48]
Reactant: COCCOc1ncccc1CO
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C#CCOc1ccc(NCc2cccnc2OCCOC)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of 400 mg (2.18 mmol) [2-(2-methoxy-ethoxy)-pyridin-3-yl]-methanol in 4 ml dioxane at r.t. is added 1.12 ml (6.55 mmol) Hünig's base followed by 170 μl (2.18 mmol) mesyl chloride and the mixture is stirred for 5 min. 641 mg (2.18 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone is added to this mixture with the addition of 1 ml of dioxane. The reaction mixture is then heated to 100° C. and stirred overnight. The mixture is partitioned between ether/water and the organic layer is washed with brine, dried with Na2SO4, filtered and evaporated. Flash-chromatography (ethyl acetate/ether 1:1) yields a yellow oil
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][CH:9]=[C:10]([S:12][C:13]#N)[CH:11]=1)=[O:6].BrC[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)(C)C>[CH2:13]([S:12][C:10]1[CH:11]=[C:7]([C:5]([O:4][CH3:3])=[O:6])[NH:8][CH:9]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1cc(SC#N)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cc(SCCc2ccccc2)c[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of sodium hydroxide (88.0 mg, 2.20 mmol) in degassed H2O (0.500 mL) was added to a mixture of 2-methoxycarbonyl-4-thiocyanopyrrole (0.200 g, 1.10 mmol), prepared according to the procedure described in J. Chem. Soc. Perkin Trans. 2 1990, 699, and (2-bromoethyl)benzene (0.165 mL, 1.21 mmol) in degassed t-BuOH (2.0 mL). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×25 mL), dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel with MeOH and CH2Cl2 (0-10% gradient) as the mobile phases to afford 0.247 g of the title compound as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 2.83-2.88 (m, 2H), 2.89-2.95 (m, 2H), 3.87 (s, 3H), 6.94-6.97 (m, 1H), 7.00 (dd, J=2.7, 1.6 Hz, 1H), 7.14-7.22 (m, 3H), 7.26-7.30 (m, 2H), 9.30 (br. s., 1H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.561 min retention time, (>95%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.535 min retention time; MS (ES) 262 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[N:30][C:31]([CH:33]([NH2:35])[CH3:34])=[CH:32][C:27]=3[N:26]=[CH:25]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH:33]([C:31]4[N:30]=[CH:29][C:28]5[N:24]([CH2:23][C:22]6[CH:36]=[CH:37][C:19]([O:18][CH3:17])=[CH:20][CH:21]=6)[CH:25]=[N:26][C:27]=5[CH:32]=4)[CH3:34])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: COc1ccc(Cn2cnc3cc(C(C)N)ncc32)cc1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2cnc3cc(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)ncc32)cc1
Temperature: 120 °C
Yield: 39.5 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (167 mg, 0.71 mmol), 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanamine (200 mg, 0.71 mmol), DIPEA (275 mg, 2.31 mmol) in 2,4-dimethylpentan-3-ol (3.0 mL) in a sealed tube was heated at 120° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by SiO2 chromatography eluting with DCM/MeOH (15:1) to 135 mg (61%) to afford 135 mg (56%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethyl)pyrimidine-2,4-diamine as white solid. MS (ESI): m/z=482.2[M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22](=[O:32])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:33])[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:31][C:26]1[CH:25]=[C:24]([NH:23][C:22]([C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C:9]4[C:8]([CH3:33])=[CH:7][C:6]([NH:5][CH2:4][CH2:3][OH:2])=[CH:11][C:10]=4[CH3:12])=[N:14][C:15]=3[CH:21]=2)=[O:32])[CH:29]=[CH:28][C:27]=1[CH3:30]
Reactant: COC(=O)CNc1cc(C)c(-c2nc3cc(C(=O)Nc4ccc(C)c(C)c4)ccc3[nH]2)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc3[nH]c(-c4c(C)cc(NCCO)cc4C)nc3c2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenylamino}-acetic acid methyl ester (80 mg) in THF (5 mL), cooled at 0° C. in an ice bath, was added LiAlH4 (1M in THF, 0.26 mL) dropwise. The mixture was warmed to room temperature. After 1 hr, the reaction was quenched with 2 drops of water and filtered. The organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography using hexanes/ethyl acetate (1:4) to afford 2-[4-(2-hydroxyethylamino)-2,6-dimethylphenyl]-1H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide as a light yellow solid. MS (ESI)m/z 429 (M+H). 1H NMR (MeOD, 400 MHz) δ 8.20 (s, 1H), 7.87 (dd, 1H), 7.67 (s, 1H), 7.48 (d, 1H), 7.43 (dd, 1H), 7.13 (d, 1H), 6.47 (s, 2H), 3.74 (t, 2H), 3.27 (t, 2H), 2.30 (s, 3H), 2.26 (s, 3H), 2.09 (s, 6H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>CC(N(C)C)=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C1CNCCNC1
Reactant: Brc1nccs1
Solvent: CC(=O)N(C)C
Product: c1csc(N2CCCNCC2)n1
Yield: 93.9 %

Procedure:
2-Bromothiazole (1.00 g, 6.10 mmol) and homopiperazine (2.44 g, 24.4 mmol) were dissolved in DMA (1 mL) and heated using a microwave (180° C., absorption high) for 30 min. The reaction mixture was dissolved in DCM (50 mL), washed with sat aq Na2CO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (1.05 g, 94%) as a yellow solid. LCMS (ES+): 184.2 [MH]+.
Reaction SMILES: [C:1]([C:3]1[CH:51]=[CH:50][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([N:33](C)[C:34](=O)OC(C)(C)C)([C:12]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(N(C)C(=O)OC(C)(C)C)(C3C(C)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)C)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl.O1CCOCC1>CO.C([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].O.CCOC(C)=O>[CH3:21][C:20]1[C:12]([C:10]([C:8]2[NH:7][C:6]3[CH:50]=[CH:51][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)([NH:33][CH3:34])[CH3:11])=[C:13]2[C:17](=[C:18]([CH3:22])[CH:19]=1)[N:16]([S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:15]=[CH:14]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)N(C)C(=O)OC(C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)N(C)C(=O)OC(C)(C)C)c(C)cc(C)c32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of (±)-tert-butyl 1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl(methyl)carbamate and (±)-tert-butyl 1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl(methyl)carbamate (95 mg, 0.130 mmol) in MeOH (326 μL) was mixed with 4 M HCl in dioxane (0.65 mL, 2.61 mmol) and the reaction stirred at 50° C. for 0.5 h. The reaction mixture was cooled to rt and diluted with 2 M aq. Na2CO3, brine and EtOAc. The products were extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 40:60) to give the title compound. MS (ESI) m/z 496.34(M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]1[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1>>[CH:28]1([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrC1C=CCCC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3C=CCCC3)CC1)O2

Procedure:
Compound 135 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-bromocyclohexene and conditions outlined in procedure V. LCMS: 382 [M+H]; Rt=0.94 min.