Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1COCC1.C(OCC)(=O)C>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([CH3:28])[CH:30]=2)([C:3]([O:2][CH3:1])=[O:17])[CH2:5][CH2:6]1)=[O:11])([CH3:14])([CH3:16])[CH3:15]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of methyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (0.25 g, 1.03 mmol; Example 3, Step B) in anhydrous THF (10 mL), a solution of sodium bis(trimethylsilyl)amide (1.2 mL, 1M, 1.2 mmol) was added over a period of 5 min. The resultant mixture was stirred at −78° C. for 1 h., and 3-methylbenzoyl chloride (135 μL, 1.02 mmol) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 8-10% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[OH-].[Na+].C(O)(=O)C>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(CC(=O)O)cc3)nc21

Procedure:
A quantity of 0.065 g (0.14 mmol) of {4-[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]phenyl}-acetic acid, methyl ester of Example 84 was dissolved in 25 mL of hot methanol with stirring. At the boiling point, 1 mL of 2N sodium hydroxide was added. After 1 hour reflux, the solution was concentrated to 5 mL volume (solid was out of solution). Water (10 mL) was added to give a complete solution. Glacial acetic acid (0.25 mL) was added to precipitate the solid free acid product. The solid was filtered, washed well with water, and dried; wt 0.060 g. Purification was accomplished by dissolution in 60 mL of 50% methanol/methylene chloride. Traces of solids were filtered, and the filtrate was concentrated with stirring to 2 mL volume. The separated solid was filtered and washed with 0.5 mL of methanol and ether; wt 0.050 g; mp 286°-290° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Cl)c1

Procedure:
A mixture of 5-methyl-2-nitrobenzoic acid (3.6 g, 19.87 mmol) and thionyl chloride (18 mL) was stirred under reflux for 20 hours then concentrated under reduced pressure to give 5-methyl-2-nitrobenzoyl chloride (3.77 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1([CH3:40])[CH3:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[C:34]([CH3:40])([CH3:39])[CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN1CCNCC1(C)C
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1(C)C

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,2-Trimethyl-piperazine following General Procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH3:19])=[C:5]2[CH2:20][C:21]([NH2:23])=[O:22].[H-].[Na+].[CH3:26][O:27][P:28]([CH2:32][CH2:33][CH2:34]Br)(=[O:31])[O:29][CH3:30].CO.CCOC(C)=O>CN(C=O)C.O>[CH3:26][O:27][P:28]([CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH3:19])=[C:5]2[CH2:20][C:21]([NH2:23])=[O:22])(=[O:31])[O:29][CH3:30]
Reactant: COP(=O)(CCCBr)OC
Reactant: CCc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
5-Hydroxy-2-ethyl-1-(phenylmethyl)-1H-indole-3-acetamide (308 mg, 1.0 mmol) was added to 40 mg (1.0 mmol) of NaH/mineral oil (washed with hexanes) in 4 mL of DMF, stirred 0.5 hours, 196 mg (0.85 mmol) of (3-bromopropyl) phosphonic acid dimethyl ester added and stirring maintained for 6.5 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel eluting with EtOAc, 5% MeOH/EtOAc, then 10% MeOH/EtOAc to give 269 mg (59% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[O:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:9][CH2:10]1)[C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: COC(=O)c1ccnc2ccc(OC)cc12
Reactant: COC(=O)CC1CCC(NC(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1ccnc2ccc(OC)cc12)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 11.3 %

Procedure:
(4-Tert-Butoxycarbonylamino-cyclohexyl)-acetic acid methyl ester (1.00 g, 3.69 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. To the solution lithium hexamethyldisilazide in tetrahydrofuran (1M, 11.0 mL, 11.0 mmol) was added dropwise. The reaction mixture was stirred for 20 minutes at −78° C. and then 6-methoxy-quinoline-4-carboxylic acid methyl ester (1.60 g, 7.38 mmol) was added as a solution in tetrahydrofuran (10 mL). The mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (2 mL), the solvent removed in vacuo and the residue partitioned between ethyl acetate (2×100 mL) and water (20 mL). The pH of the aqueous phase was adjusted to 10 to obtain the maximum degree of extracted material into the organic phases. The organic phases were combined, dried over magnesium sulfate and the volatiles removed under suction. The resulting residue was purified by column chromatography on silica gel using an ethyl acetate and hexane solvent gradient to provide the desired compound as a colourless oil (190 mg, 12%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[OH:53])[CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1)#[N:24]>C(#N)C>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[O:53][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH:4]=2)[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: ClCc1ccc(CCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(CCc3ccccc3)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 70 %

Procedure:
460 mg (2 mmol) of 1-(chloromethyl)-4-(2-phenylethyl)benzene [preparation according to M. Carrara et al., Arzneim. Forsch. 47 (7), 803-809 (1997)] and 414 mg (3 mmol) of anhydrous potassium carbonate are added to a solution of 411 mg (1 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then evaporated to dryness. The residue is taken up in ethyl acetate, washed with water and with saturated sodium chloride solution and dried over sodium sulphate. After filtration, the organic phase is evaporated and the resulting crude product is purified by preparative HPLC. 431 mg (0.7 mmol, 65% yield) of a solid are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:9][OH:10])[CH3:8])=[CH:3][CH:2]=1.[BH4-].[Na+].[CH3:13]O>>[CH3:13][N:1]1[CH2:6][CH:5]=[C:4]([C:7](=[N:9][OH:10])[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(=NO)c1ccncc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(=NO)C1=CCN(C)CC1
Reaction time: 1 h

Procedure:
A solution of 1-(4-pyridinyl)ethanone oxime, methiodide (48.36 g, 174 mmol) in 200 ml of 50% aqueous methanol was added to a cooled (-5° C.) slurry of sodium borohydride (12.86 g, 340 mmol) in 200 ml 50% aqueous methanol and the reaction mixture was stirred one hour. After some inorganic material was removed by filtration, the methanol was distilled off the filtrate in vacuo. The resulting solid was collected by filtration and dried to provide 1-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)ethanone oxime (18 g), mp 166°-168° C.
Reaction SMILES: C(OC(OCC)C1C=CC=C2C=1SC1C(C=O)=CC=CC=1N2C)C.CS(CSC)=O.C(C1C=CC=C2C=1SC1C(CC(OC)=O)=CC=CC=1N2C)=O.C([O-])(=O)C.[Na+].[ClH:58].NO.[N:61](=[CH:63][C:64]1[CH:77]=[CH:76][CH:75]=[C:74]2[C:65]=1[S:66][C:67]1[C:68]([CH2:79][C:80]([O:82][CH3:83])=[O:81])=[CH:69][CH:70]=[CH:71][C:72]=1[N:73]2[CH3:78])O.Cl>O1CCCC1.CO.[Pd].O>[ClH:58].[NH2:61][CH2:63][C:64]1[CH:77]=[CH:76][CH:75]=[C:74]2[C:65]=1[S:66][C:67]1[C:68]([CH2:79][C:80]([O:82][CH3:83])=[O:81])=[CH:69][CH:70]=[CH:71][C:72]=1[N:73]2[CH3:78]
Reactant: COC(=O)Cc1cccc2c1Sc1c(C=NO)cccc1N2C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCOC(OCC)c1cccc2c1Sc1c(C=O)cccc1N2C
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cccc2c1Sc1c(CN)cccc1N2C

Procedure:
A solution of 500 mg (1.46 mmol) of 6-diethoxymethyl-10-methyl-phenothiazine-4-carbaldehyde in 5 ml of tetrahydrofuran can be converted analogously to that described in Example 1.1.1.d with 0.22 g (1.75 mmol) of methyl (methylthiomethyl)sulphoxide, 0.14 ml of Triton B solution (35% in methanol) and hydrolysis into methyl 6-formyl-10-methyl-phenothiazine-4-acetate. This compound can be converted analogously to that described in Example 1.1.1.e in methanol, water and tetrahydrofuran using sodium acetate and hydroxylamine hydrochloride into methyl 6-[(hydroximino)methyl]-10-methyl-phenothiazine-4-acetate. This compound can be hydrogenated over palladium/charcaol in methanol and methanolic hydrochloric acid (20%) analogously to that described in Example 1.1.1.f, whereby there is obtained methyl 6-aminomethyl-10-methyl-phenothiazine-4-acetate hydrochloride which can be converted analogously to that described in Example 1.1.2 in dioxan and 1N sodium hydroxide solution using di-tert-butyl dicarbonate into methyl 6-[(1-tert-butylformamido)methyl]-10-methyl-phenothiazine-4-acetate. The product obtained can be hydrolyzed with 1N potassium hydroxide solution in methanol analogously to that described in Example 1.1.3 to give (6-tert-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetic acid prepared according to Example 2.1.1.g.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[CH:27]12[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:32]1[CH2:31][CH2:30][NH:29][CH2:28]2>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:29]3[CH2:30][CH2:31][CH:32]4[CH:27]([N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33]4)[CH2:28]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C=O)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CC2CCNCC21
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCC4CN(C(=O)OC(C)(C)C)C4C3)cc2)n1

Procedure:
Title compound was prepared as a white solid (64 mg, 58.1% yield), with procedures similar to those used to prepare Intermediate 128, but utilizing 4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde and tert-butyl 3,8-diazabicyclo[4.2.0]octane-8-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].CO>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C@@H:11]([OH:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Temperature: -10 °C

Procedure:
To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-methyl CBS oxaborolidine (7.4 mL of a 1 M soln in toluene, 7.4 mmol, Aldrich). Toluene 190 mL was added and the reaction was cooled in an ice-salt bath (bath temp.=−10° C.). BH3-SMe2 was added (17 mL, 180 mmol, Aldrich), then 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over 5 h using a syringe pump. After the addition was complete, the mixture was stirred for an additional 1 h. The mixture was poured into an addition funnel, and the mixture was added to 200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate that the internal temp. was kept below 0° C. The mixture was concentrated in vacuo. Et2O (1L) was added, and the mixture was washed with 1 M H3PO4 (3×), satd NaHCO3, and brine (ca. 400 mL each wash). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in Et2O again (500 mL), and the mixture was washed with 1M H3PO4 (3×200 mL), satd NaHCO3, and brine. After drying the organic layer over MgSO4, the mixture was filtered and concentrated in vacuo, which gave the title compound as a white-yellow solid. MS (+ion ESI) m/z=207 (MH+), 189 (MH+-H2O).
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P([CH:27]1[CH2:32][CH2:31]CCC1)(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C>[CH:31]1([C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:32][CH2:27]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1C1CC1
Temperature: 25 °C
Yield: 645.6 %

Procedure:
A solution of 2-bromo-3-nitrobenzoic acid (1.17 g, 4.28 mmol), Pd(OAc)2 (0.048 g, 0.21 mmol), P(Cy)3 (0.132 g, 0.471 mmol), K3PO4 (3.18 g, 15.0 mmol) and cyclopropylboronic acid (0.735 g, 8.56 mmol) in toluene (4 mL) and water (1 mL) was stirred at 100° C. for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to about pH 3-4. The resulting solid was collected by filtration to give 2-cyclopropyl-3-nitrobenzoic acid (0.63 g, 71.0%) as a solid.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11])([OH:3])=[O:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:10]([CH2:9][O:8][C:7]1[CH:13]=[C:14]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:15]=[CH:16][C:6]=1[O:5][CH2:4][C:1]([OH:3])=[O:2])([OH:12])=[O:11]
Reactant: O=C(O)COc1ccccc1OCC(=O)O
Reactant: O=S(=O)(O)Cl
Product: O=C(O)COc1ccc(S(=O)(=O)Cl)cc1OCC(=O)O
Temperature: 25 °C

Procedure:
2-Carboxymethoxyphenoxyacetic acid (15.3 g, 0.0675 mol) was added in portions over 30 min to stirred chlorosulfonic acid (59.0 g, 0.506 mol) that was cooled in an ice/methanol bath. The mixture was allowed to warm to room temperature over 2.5 hr and was then poured slowly into stirred ice water. The resulting solid was collected by filtration, washed with water, and dried at high vacuum over sodium hydroxide. The product, title compound, weighed 6.54 g (30%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][CH2:11][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][O:14][CH3:15])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:25][C:26]1[S:30][N:29]=[C:28]([CH3:31])[CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][CH2:11][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][O:14][CH3:15])=[CH:3][C:2]=1[NH:25][C:26]1[S:30][N:29]=[C:28]([CH3:31])[CH:27]=1)#[N:9]
Reactant: Cc1cc(N)sn1
Reactant: COC[C@@H](CNc1ccc(C#N)c(Br)c1)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC[C@@H](CNc1ccc(C#N)c(Nc2cc(C)ns2)c1)NC(=O)OC(C)(C)C
Temperature: 120 °C

Procedure:
A mixture of (R)-tert-butyl 1-(3-bromo-4-cyanophenylamino)-3-methoxypropan-2-ylcarbamate (150 mg, 0.39 mmol), 5-amino-3-methylisothiazole hydrochloride (76 mg, 0.51 mmol), BINAP (25 mg, 0.04 mmol), Pd(OAc)2 (18 mg, 0.08 mmol) and K2CO3 (188 mg, 1.37 mmol) p-dioxane (3 mL) was degassed with Ar, then was heated at 120° C. for 15 h. the mixture was filtered, filter cake was washed with EtOAc, and the filtrated was concentrated in vacuo to give (R)-tert-butyl 1-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-methoxypropan-2-ylcarbamate as crude oil.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: Fc1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed in 400 ml of toluene that contained 3.5 g of morpholine and 3.10 g of 4-fluorobenzaldehyde that had been freshly washed in K2CO3. The reaction mixture was refluxed over two (2) nights and then concentrated, purified by flash chromatography (20% EtOAc/CH2Cl2) and recrystallized from dichloromethane/pentane to give 2.20 g of analytically pure product, m.p. 161°-163° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([NH2:14])=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.I[CH:16]([CH3:18])[CH3:17].C[O-].[Na+]>C1COCC1>[CH:16]([N:12]1[CH:13]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[C:10]([NH2:14])=[N:11]1)([CH3:18])[CH3:17]
Reactant: CSc1nccc(-c2c[nH]nc2N)n1
Reactant: CC(C)I
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2cn(C(C)C)nc2N)n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
Intermediate 4-(2-(Methylthio)pyrimidin-4-yl)-1H-pyrazol-3-amine (10.0 g, 40 mmol) was dissolved in THF (200 mL), followed by addition of 2-iodopropane (6.3 mL, 63 mmol) and sodium methoxide (25% weight solution in methanol, 14.3 ml, 63 mmol). The mixture was heated at 50° C. with stirring under a nitrogen atmosphere for 3 d, then was concentrated under vacuum. The residue was taken up in ethyl acetate (200 mL) and washed with aqueous potassium carbonate solution and brine, then dried over sodium sulfate, filtered, and concentrated to provide a brown residue. The residue was chromatographed on silica gel (hexane/ethyl acetate eluant) to provide 1-isopropyl-4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-3-amine as a solid; 1H NMR 400 MHz (CDCl3) δ 8.23 (d, J=5.6 Hz, 1H), 7.60 (s, 1H), 6.83 (d, J=5.6 Hz, 1H), 5.23 (d, J=2.8 Hz, 2H), 4.21-4.25 (m, 1H), 2.50 (s, 3H), 1.37 (d, J=6.8 Hz, 6H); MS m/z: 250.1 (M+1).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:6]2[NH:5]1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:5]1[C@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2NC(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a suspension of sodium hydride (17 mg of 60% dispersion in mineral oil, hexane-washed, 0.42 mmol) in 2 mL of THF was added (3aR,9bS)-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 13, Part A (101 mg, 0.28 mmol) in 2 mL of THF. The resulting mixture was stirred at ambient temperature for 30 min, at which time gas evolution has ceased. Then there was added methyl bromoacetate (0.053 mL, 0.56 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The reaction was quenched with 10 mL of 1 N HCl and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 120 mg (99%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 429.22 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c[nH]c13)OCO2

Procedure:
Starting from trans-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A185) and acetyl chloride the title compound was obtained as colorless solid.