Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]=[C:42]=[O:43]>ClCCl>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)=[O:43]
Reactant: COc1ccccc1N=C=O
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 2-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (2-methoxy-phenyl)-amide as a white solid. (Yield 45 mg, 64%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[SH:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>O>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([S:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[C:15]([F:14])[CH:16]=1)#[N:19]
Reactant: Sc1cccs1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccs2)c(F)c1
Temperature: 25 °C

Procedure:
Sodium hydride (1.80 g 60% dispersion in oil, 0.045 mol) was washed with petroleum ether then suspended in freshly degassed DMF (50 ml). Thiophene thiol (5.22 g, 0.045 mol) was added dropwise under nitrogen and the mixture was stirred until gas evolution ceased. 3,4-Difluorobenzonitrile (5.0 g, 0.036 mol) was added portionwise and the mixture was refluxed about 1.5 hours, after which the mixture was cooled to room temperature. The reaction mixture was poured into cold H2O and extracted with 3×100 ml ether. The ether extracts were washed with water and brine, then treated with decolorizing carbon and magnesium sulfate. After filtration and evaporation of the solvent the residual (8.46 g) oil crystallized.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[C:16]([CH3:19])[C:17]([OH:18])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18]
Reactant: Cc1cc(N)cc(Cl)c1O
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1cc(Nc2ncc(F)c(Nc3cc(C)c(O)c(Cl)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-hydroxy-5-methylaniline gave N2,N4-bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.55 min.; purity: 99%; MS (m/e): 410 (MH+); 1H NMR (DMSO-d6): δ 9.23 (1H, s), 9.07 (1H, s), 8.99 (1H, s), 8.66 (1H, s), 8.13 (1H, d, J=3.6 Hz), 7.59 (2H, t, J=3.1 Hz), 7.50 (1H, d, J=2.3 Hz), 7.34 (1H, d, J=2.3 Hz), 2.27 (3H, s), 2.18 (3H, s).
Reaction SMILES: [OH-].[Na+].[C:3]([SH:7])([CH3:6])([CH3:5])[CH3:4].Cl[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1>CO>[Cl:16][C:11]1[CH:10]=[C:9]([CH2:4][C:3]([S:7][C:3]([CH3:6])([CH3:5])[CH2:4][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)([CH3:6])[CH3:5])[CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: CC(C)(C)S
Reactant: Clc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1cc(Cl)cc(Cl)c1)SC(C)(C)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
To a solution of sodium hydroxide (120 mg, 3 mmol, in oil, 60% cont.) in anhydrous methanol (5 ml) was added tert-butyl mercaptan (0.406 ml). The mixture was stirred for 20 minutes at room temperature. The reaction mixture was concentrated dryness under reduced pressure. The obtained sodium isopropylmercaptan was dissolved in HMPT (2 ml). 1,3,5-trichlorobenzene (1) (1.8 g, 10 mmol) was added thereto. The mixture was stirred for 2 hours and 50 minutes at 80° C. The reaction mixture was poured into ice-water. The mixture was extracted with ethylacetate, washed with water, dried over sodium sulphate, filtrated and concentrated under reduced pressure. The obtained residue was chromatographed twice on silica gel (SiO2 15 g, elution: n-hexane) to yield the objective (4) (293 mg). Yield 41%.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:35][O:27][C:26]4[CH:25]=[C:24]5[C:19](=[CH:18][C:17]3=4)[CH2:20][CH2:21][CH2:22][CH2:23]5)[C:9]2=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)CCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCC3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1H)-one was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.37-7.32 (m, 10H), 7.17-7.14 (m, 1H), 7.07 (s, 1H), 7.05-6.94 (m, 2H), 6.67 (s, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 4.96 (d, J=8.9 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 2.73 (br s, 2H), 2.54 (br s, 1H), 1.72-1.70 (m, 4H); MS (ES+) m/z 457.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][N:35]=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[C:43](Cl)(=[O:45])[CH3:44].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:35]=[CH:36][C:37]([NH:40][C:43](=[O:45])[CH3:44])=[CH:38][N:39]=2)[C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N)cn2)C[C@H]1CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(NC(C)=O)cn2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R*,4S*)-4-{(5-Aminopyrimidin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (4 ml), then thereto are added acetyl chloride (0.03 ml) and triethylamine (0.1 ml), and the mixture is stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→1:1) to give (2R*,4S*)-4-{(5-acetylaminopyrimidin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 641 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH3:25])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: CI
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cccc(-c2csc3cnc(Cl)nc23)c1)S(C)(=O)=O
Yield: 93.4 %

Procedure:
N-(3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (200 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) and sodium hydride (36 mg, 0.89 mmol) was slowly added at 0° C. 10 minutes later, after adding iodomethane (100 mg, 0.71 mmol), the reaction mixture was stirred for an hour, diluted with ethyl acetate, and washed with brine. The organic layer was dried with magnesium sulfate, filtered, and then concentrated. The target compound (195 mg, 94% yield) was obtained without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:28]=1[O:29][C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][C:28]=3[O:29][C:30]3[N:31]=[CH:32][CH:33]=[CH:34][N:35]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc(Br)c(Oc2ncccn2)c1
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccc(C(F)(F)F)cc2Oc2ncccn2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidine. MS (ESI): mass calcd. for C22H12F4N6O, 452.10; m/z found, 453.1 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.56 (d, J=4.8, 2H), 8.20 (s, 1H), 7.89-7.81 (m, 2H), 7.81-7.75 (m, 1H), 7.61-7.54 (m, 1H), 7.48 (dd, J=11.1, 1.7, 1H), 7.43 (dd, J=8.1, 1.7, 1H), 7.37 (s, 2H), 7.22-7.17 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]=[CH:10][N:11](C)C)=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].N[C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(SCC)=NC=1)#N>>[CH2:22]([O:21][C:19]1[CH:18]=[CH:17][C:16]([S:29][C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)=[C:15]([NH:2][C:1]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][CH:8]=3)[N:9]=[CH:10][N:11]=2)[CH:20]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncncc1C#N
Agent: CCSc1ncc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ncnc3ncncc23)cc1

Procedure:
The product from Example 194A was reacted with the product from Example 27A according to the procedure from Example 156C substituting the product from Example 27A for the product from Example 6c and substituting the product from Example 194A for the product from Example 156B to provide the crude product which was purified by HPLC with NH4OAc to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 2H), 6.63 (d, J=8.46 Hz, 2H), 6.94-7.05 (m, 1H), 7.10 (d, J=8.82 Hz, 2H), 7.18 (d, J=7.72 Hz, 2H), 7.29-7.51 (m, 5H), 9.05 (m, 1H), 9.63 (s, 1H), 9.92 (s, 1H), 10.66 (s, 1H); MS (ESI−) m/z 452 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[NH:16]1[CH:20]=[CH:19][NH:18][C:17]1=[S:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:14][C@@H:3]1[C@H:4]([S:21][CH:17]2[N:18]=[CH:19][CH:20]=[N:16]2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: S=c1[nH]cc[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](SC2N=CC=N2)[C@H]1O

Procedure:
(S,S)-2,2-Dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile (1 mmoL), 1,3-dihydro-imidazole-2-thione (1 mmoL) and anhydrous K2CO3 (1.5 mmoL) in DMF (5 mL) were heated at 100° C. for 4˜6 hrs. The solid was filtered off and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NH4Cl, brine, then dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil. Silica gel chromatography separation yielded the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)#[N:2].CO.[ClH:17].CO[CH:20](OC)[CH2:21][NH2:22]>CCOCC>[ClH:17].[NH:2]1[CH:20]=[CH:21][N:22]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CCC#N)cc1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc(CCc2ncc[nH]2)cc1

Procedure:
Nitrile 23-3 (400 mg, 2.11 mmol) was dissolved in 10 mL Et2O at 0° MeOH (289 μL, 4.2 mmol) was added, the mixture was saturated with anhydrous HCl. Once the white ppt. formed, the solvent was evaporated and replaced with MeOH (5 mL), cooled to 0°, and aminoacetaldehyde dimethylacetal (250 μL, 2.3 mmol) was added. The reaction was heated to reflux for 3 days then concentrated, diluted in 10 mL 6N HCl and concentrated again providing 23-4 as a solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].CCOCC>ClCCl>[F:12][C:13]1[CH:18]=[C:17]([S:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:9])[CH:16]=[CH:15][C:14]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:30])[F:31]
Reactant: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1F)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)c2ccccc2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
m-Chloroperbenzoic acid (55%, 0.157 g) was added to a solution of (R)-N-[2-fluoro-4-(phenylthio)phenyl]2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 7) (0.212 g) in dichloromethane (5 ml) and the mixture was stirred at ambient temperature for 90 minutes. Ether (20 ml) was added and the solution was washed with saturated aqueous sodium carbonate solution (2×10 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 20-30% ethyl acetate/hexane to give the title compound (0.138 g) as a gum. NMR: 1.55 (s, 3H), 7.5-7.6 (m, 4H), 7.66 (d, 1H), 7.74 (m, 2H), 7.87 (t, 1H), 9.8 (br s, 1H); MS: 374 (M−H)−.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(CN)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)OC
Yield: 78.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2,2-dimethoxy-ethyl)-amide (700 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (716 mg), 2,2-dimethoxy-ethylamine (265 mg), HBTU (952 mg), and DIEA (700 uL) in DMF (5 mL).
Reaction SMILES: CO[C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[CH3:15]OC1C=C2C(=CC=1)C(CCN)=CN2.C(O)(C(F)(F)F)=O>C1COCC1>[CH2:15]1[C:8]2[NH:7][C:6]3[C:13](=[CH:14][CH:3]=[CH:4][CH:5]=3)[C:9]=2[CH2:10][CH2:11][NH:12]1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc2c3c([nH]c2c1)CNCC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Methoxy tryptamine 1a or 6-methoxy tryptamine 1b (0.524 mmol) and appropriate aryl or heteroaryl aldehyde 2 (0.63 mmol) were dissolved in THF (20 mL). The reaction mixture was cooled to 0° C. CF3COOH (0.2 ml) was then added at 0° C., and the reaction mixture was then allowed to stir at 0° C. for 1 hr. The ice bath was then removed and the reaction allowed to stir for a further 1 hr from 0° C. to r.t. The reaction mixture was quenched with aqueous saturated NaHCO3 (5 ml) and the organic phase separated. The mixture was extracted with EtOAc (2×10 ml). The combined organic phase was dried (anhydrous NaSO4), filtered and evaporated in vacuo to give the crude product tetrahydro β-carboline 3. The crude product was directly used for second step with out further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.[CH3:45][O:46]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.COC1C=CC(B(O)O)=CC=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([O:46][CH3:45])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(OC)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 15 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-methoxyphenylboronic acid (40 mg, 0.2625 mmol) to produce the title compound (15 mg, 15% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][N:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:23]([C:22]2[C:17]([S:16][CH2:14][CH3:15])=[N:18][CH:19]=[N:20][CH:21]=2)=[O:24])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CCSc1ncncc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ncncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 1.04 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 1.00 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid, 1.57 g of EDCI hydrochloride, 73 mg of HOBt and 5 ml of pyridine was stirred at 60° C. for 4 hours. Water was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.94 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanylpyrimidine-5-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: C([O:9][C:10]1[C:11]([C:35]([O:37]C)=O)=[N:12][C:13]([CH:17]([NH:27]C(OC(C)(C)C)=O)[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14][C:15]=1[OH:16])(=O)C1C=CC=CC=1.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>>[NH2:27][CH:17]([C:13]1[N:12]=[C:11]([C:35]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=2)=[O:37])[C:10]([OH:9])=[C:15]([OH:16])[N:14]=1)[CH2:18][O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1nc(C(COCc2ccccc2)NC(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Product: NC(COCc1ccccc1)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a methanolic solution of methyl 5-(benzoyloxy)-2-{2-(benzyloxy)-1-[(tert butoxycarbonyl)amino]ethyl}-6-hydroxypyrimidine-4-carboxylate prepared as described in Step 2, 4-fluorobenzylamine (2.15 eq.) was added. The resulting solution was refluxed for 24 hours (100% conversion by LC-MS). After cooling to room temperature, the crude was concentrated under reduced pressure and the solvent switched to CH2Cl2. To the solution, trifluoroacetic acid was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and diethyl ether (100 mL) was added. The resulting slurry was stirred for 1 hour at room temperature and the product was collected by filtration. The cake was washed with cold diethyl ether and dried under reduced pressure to afford title compound as trifluoroacetic salt. MS (ES) C21H21FN4O4 requires 412. Found: 413.