Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:32]#[N:33])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:34]=[C:35](Br)[CH:36]=[N:37][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>[Pd].ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:32]#[N:33])=[C:18]([O:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:25]4)[C:13]=3[C:12]3[CH:34]=[CH:35][CH:36]=[N:37][C:11]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A suspension of 9-benzenesulfonyl-3-bromo-5-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (245 mg, 0.39 mmol) and palladium on carbon (10 wt %, 50 mg) in industrial methylated spirits (5 mL), dichloromethane (5 mL), and triethylamine (3 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 24 hours. The reaction vessel was purged with nitrogen then the reaction mixture was filtered through a PTFE filter cup. The filtrate was evaporated in-vacuo and the resultant residue purified by flash chromatography (silica, 10 g column, ISCO, 0-50% ethyl acetate in dichloromethane) to afford the title compound as an off-white solid (140 mg, 65%). LCMS (Method C): RT=4.97 min, M+H+=400. 1H NMR (300 MHz, DMSO-d6): 9.49 (s, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 8.63 (dd, J=7.9, 1.7 Hz, 1H), 8.25-8.24 (m, 2H), 7.76 (t, J=7.4 Hz, 1H), 7.64-7.63 (m, 3H), 4.76-4.75 (m, 1H), 3.26 (t, J=7.4 Hz, 2H obscured by solvent peak), 3.02 (s, 3H), 2.88 (d, J=11.3 Hz, 2H), 2.72 (t, J=6.8 Hz, 2H), 2.14-2.14 (m, 4H), 1.91-1.91 (m, 2H).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH:13]([C:26]([OH:28])=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[OH-:29].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O>[C:1]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]3[C:18]([NH:23][C:26](=[O:28])[CH:13]2[CH2:12]1)=[CH:19][CH:20]=[CH:21][CH:22]=3)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:29]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Reaction time: 2.5 h

Procedure:
To a solution of 13 g. of 4-carbobenzoxy-1-(o-nitrophenyl)piperazine- 2-carboxylic acid and 11.0 g. of sodium hydroxide in 200 ml. of water is added a solution of 20 g. of sodium hydrosulfite in 200 ml. of H 2 O. The orange solution gradually turns colorless over a period of 2-3 hours. Dilute hydrochloric acid is added to bring the pH of the solution to about 3. A white precipitate forms. Stirring is continued for about 3-5 minutes, and the pH is raised to about 7 by the addition of 40% sodium hydroxide. Filtration gives 8.6 g. of product, m.p. 125°-140°. The analytical sample on recrystallization from ethyl acetate hexane gave a m.p. 167°-170°.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20](/[C:23](/[CH3:30])=[CH:24]/[C:25](OCC)=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20](/[C:23](/[CH3:30])=[CH:24]/[CH2:25][OH:26])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(F)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The colourless solid (E)-3-(4′-fluoro-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(4′-fluoro-biphenyl-4-yl)-but-2-enoate as described for example 52b.
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([CH3:30])([CH3:29])[O:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([NH:21]C(=O)OC(C)(C)C)[CH:8]=2)#[N:3].[O:31]1CCOCC1>>[NH2:21][C:9]1[CH:8]=[C:7]2[C:12]([C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:4]([C:2]([NH2:3])=[O:31])[C:5]([CH3:30])([CH3:29])[O:6]2)=[CH:11][CH:10]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(C#N)=C2c1ccc(F)cc1
Agent: Cl
Product: CC1(C)Oc2cc(N)ccc2C(c2ccc(F)cc2)=C1C(N)=O

Procedure:
6N Hydrochloric acid (15 mL) was added to a solution of tert-butyl [3-cyano-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]carbamate (a compound obtained in Reference Example 8(3); 150 mg) in dioxane (5 mL) and the mixture was heated under reflux for 90 hours. The reaction solution was concentrated in vacuo, the resulted residue was diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate and brine. The organic layer was filtered through a column of porous diatomite (Chem Elut) and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: chloroform/methanol=100/0 to 95/5) to give the titled compound (26 mg) as a yellow powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[O:19]=[C:10]1[CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CCNCC1=O
Yield: 118 %

Procedure:
Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate 1 (15.0 g, 50.5 mmol, 1.0 equiv) was hydrogenated in the presence of 10% Pd/C (1.5 g) catalyst under H2 at atmospheric pressure in MeOH (250 mL) for 16 h. The catalyst was filtered off and the solvent was concentrated in vacuo to give ethyl 3-oxopiperidine-4-carboxylate 2 as a light yellow solid (10.2 g, yield: 98.0%). ESI-MS (M+H)+: 172.1. 1H NMR (400 MHz, DMSO-d6) δ: 4.23 (q, 2H), 3.75 (s, 2H), 3.37 (s, 2H), 3.20-3.16 (m, 2H), 2.44 (t, 1H), 1.25 (t, 3H).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[CH:16][C:17]=3[CH3:21])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:26])(=O)=O>>[Cl:26][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([CH3:22])[CH:15]=[CH:16][C:17]=2[CH3:21])[S:10]1(=[O:12])=[O:11]
Reactant: Cc1ccc(C)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Product: Cc1ccc(C)c2c1C(=O)N(CCl)S2(=O)=O
Yield: 51 %

Procedure:
The 0.07 g sample of material obtained in the early fractions from the chromatographic separation described above in Preparation 16A consisting predominantly of 2-phenylthiomethyl-4,7-dimethylsaccharin was reacted with 0.05 ml of sulfuryl chloride in MDC and the product recrystallized from cyclohexaneethyl acetate to give 20 mg (51%) of 2-chloromethyl-4,7-dimethylsaccharin, mp 107°-108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO.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>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Nc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 100 °C
Yield: 66.9 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (0.5 g, 2.79 mmol) and [4-(methylsulfonyl)phenyl]boronic acid (0.57 g, 2.79 mmol) in 1,4-dioxane (10 mL) and MeOH (4 mL) was treated with 2M Na2CO3 (4 mL) and Pd(PPh3)4 (65 mg, 0.06 mmol). The reaction mixture was degassed with N2 and heated at 100° C. for 3 h. Most of 1,4-dioxane and MeOH was removed under reduced pressure. Water was added, and the mixture was extracted with EtOAc (50 mL×4). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid, which was triturated with CH2Cl2 to give 0.465 g (67%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellow solid. The filtrate was washed with 1 N HCl (25 mL), and the aqueous layer was separated and basified with 4N NaOH. The mixture was extracted with EtOAc (50 mL×2) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give additional 0.045 g (7%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.15 (d, 2H, J=8.5 Hz), 7.97 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 6.81 (s, 2H), 3.20 (s, 3H); LRMS (ESI), m/z 250 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:27]=[C:26]([CH3:36])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:27]=[C:26]([CH3:36])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCCC2)n1
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCCC2)n1
Yield: 57.1 %

Procedure:
((2R)-2-(Cyclopentylmethyl)-3-{2-[5-fluoro-2-methyl-6-(1-pyrrolidinyl)-4-pyrimidinyl]hydrazino}-3-oxopropyl)[(phenylmethyl)oxy]formamide (90 mg, 0.18 mmol) was dissolved in 3 mL of MeOH, degassed and placed under argon. 10% Pd/C (18 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 3 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. The resulting filtrate was concentrated in vacuo to provide the pure ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-2-methyl-6-(1-pyrrolidinyl)-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide (42 mg, 57%). LCMS: (M+H)+: 407.6.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[CH:13][C:12]=2[O:21][CH2:22][CH:23]([F:25])[F:24])[CH2:5][CH2:4]1>[Pd]>[F:1][C:2]([F:27])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[CH:13][C:12]=2[O:21][CH2:22][CH:23]([F:24])[F:25])[CH2:5][CH2:4]1
Reactant: Nc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
The subtitle compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(2,2-difluoro-ethoxy)-4-amino-5-nitro-benzoic acid amide with Pd/C and H2 in analogy to example 1f.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@:11]([NH:34]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:18]=2)[C:10]1=[O:42].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:34][C@:11]1([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:42]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(N)CCN(C)C2=O)n1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Trifluoroacetic acid (2 mL, 26.92 mmol) was added to a solution of tert-butyl N-[(3R)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 13) (482 mg, 0.99 mmol) in DCM (10 mL) at 20° C. and the reaction was stirred for 1 hour. Solid K2CO3 was added to quench the TFA present (care: gas evolved) and the resultant solid was filtered off and washed five times with DCM. The solvent was evaporated to give (3R)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (D14) (343 mg, 0.883 mmol, 89.5% yield) as a yellow oil. 300 MHz NMR δH (CDCl3) 1.95 (2H, br.s), 2.07-2.17 (1H, m), 2.44-2.53 (1H, m), 2.63 (3H, s), 2.72-2.88 (2H, abq), 2.94 (3H, s), 3.38-3.53 (2H, m), 7.53 (1H, s), 7.78 (2H, d), 8.20 (2H, d).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:22])=[CH:17][CH:16]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCN2CCOCC2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 4-(3-aminopropyl)morpholine (22.5 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanoltriethylamine (96:2:2). Concentration of the product fractions under vacuum N-(6-methyl-4′-{[(3-morpholin-4-ylpropyl)amino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (59.5 mg, 83%). NMR; δH [2H6]-DMSO 9.94,(1H, s), 8.55,(1H, t), 8.36,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 7.67,(1H, dd), 7.60,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.98,(1H, m), 3.56,(4H, t), 3.30,(2H, m), 2.35–2.32,(6H, m), 2.19,(3H, s), 1.69,(2H, m). LCMS: retention time 2.42 min, MH+448.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([NH:7][C@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:22][CH:23]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc3ccccc23)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A 5 ml vial was charged with Cs2CO3 (654 mg, 3.3 mmol) and was dried in vacuo at 60° C. for two hours. Palladium acetate (31.5 mg, 0.14 mmol), BI NAP (43 mg, 0.07 mmol) were added followed by anhydrous dioxane (2 ml). The mixture was sonicated for one hour after which tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (186.3 mg, 1.0 mmol) and 4-chloroquinoline (163 mg, 1 mmol) dissolved in 2 ml anhydrous dioxane were added. The mixture was stirred at 100° C. overnight. The reaction mixture was purified directly by column chromatography (prepacked silica column, gradient heptan/ethyl acetate). 231 mg (0.68 mmol, 68%) of a solid were obtained. MS (APCI): m/z=314.0 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[CH:12][CH:11]=1)([O-])=O>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccno1
Agent: Cl
Product: Nc1ccccc1-c1ccno1
Temperature: 105 °C
Yield: 30.5 %

Procedure:
5-(2-nitrophenyl)isoxazole (850 mg, 4.5 mmol), prepared as in Example 101, was added portionwise to a suspension of stannous chloride dihydrate (3.3 g, 14.6 mmol) in concentrated hydrochloric acid (8.3 mL). The reaction was heated to 105° C. four 1 hour. The reaction was cooled to 10° C. and filtered, and the solid was added to water (10 mL). The solution was adjusted to pH 10 with 10N sodium hydroxide, and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 5-(2-aminophenyl)isoxazole (220 mg), which was coupled with CMI under conditions described in the general procedure for CMI coupling to give the hydrochloric acid salt of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(5-isoxazolyl)aniline.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.O[CH2:25][CH2:26][N:27](C)[C:28](=O)OC(C)(C)C.Cl>CO>[CH3:28][NH:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Agent: Cl
Solvent: CO
Product: CNCCOc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and tert-butyl 2-hydroxyethyl(methyl)carbamate except that the crude product was deprotected with a mixture of MeOH (1 mL) and conc. HCl (1 mL) before purification. MS (ESI) m/z 361.12 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.29 (1H, d, J=8.85 Hz), 8.16 (1H, s), 8.11 (2H, d, J=7.02 Hz), 7.54 (2H, t, J=7.78 Hz), 7.44 (1H, t, J=7.32 Hz), 7.21 (1H, d, J=2.14 Hz), 6.98 (1H, dd, J=8.70, 2.29 Hz), 4.25 (2H, t, J=5.19 Hz), 3.05 (2H, t, J=5.19 Hz), 2.51 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([O:18]CC)=[O:17])=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
Ethyl 1-(4-chlorobenzyl)-1H-indole-2-carboxylate (2.00 g, 6.37 mmol) and lithium hydroxide (1.53 g, 63.7 mmol) were dissolved in THF:water (10 mL: 20 mL). The reaction was heated at 60° C. overnight. The reaction was cooled and further diluted with water. The reaction was transferred into a separatory funnel and was washed with diethyl ether. The aqueous layer was acidified using 2N HCl to pH 2 where a white solid formed. The suspension was returned to the separatory funnel and was washed with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain pure product as a white solid. Yield: 1.47 g, (White solid).
Reaction SMILES: [CH:1]1([CH:6]([OH:17])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[O:17]=[C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(OCc1ccccc1)C(O)C1CCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a solution of benzyl 2-cyclopentyl-2-hydroxyacetate (1.76 g, 7.5 mmol) in dichloromethane (30 mL) was added Dess-Martin reagent (5 g, 11.8 mmol), and the mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with 10% sodium thiosulfate, and extracted with diethyl ether. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, and brine, dried over anhydrous magnesium sulfate, filtered, and the organic solvent in the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1) to give 1.383 g of the title compound as oil (yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19][CH:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>>[CH3:19][CH:20]([S:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:24])=[O:23])[CH3:21]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Product: CC(C)S(=O)(=O)Nc1cccc(OCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) using propane-2-sulfonyl chloride following the method described in Example 1 gave tert-butyl 2-(3-(1-methylethylsulfonamido)phenoxy)ethylcarbamate (7) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.97 (t, J=6.0 Hz, 1H), 6.76-6.79 (m, 2H), 6.60-6.62 (m, 1H), 3.16-3.30 (m, 3H), 1.35 (s, 9H), 1.19 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH:8][C:9]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:13]3[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[N:3]1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([N:8]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:13]3[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[N:3]1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1nc(Nc2nc(C)n(C)n2)c2ncc(C#N)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(C)n(C)n2)c2nc(SC)nn3c(C#N)cnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (157 mg, 0.521 mmol) was taken up in DMF (6 mL) under argon and NaH (22.92 mg, 0.573 mmol) was added. The reaction mixture was stirred at rt for 30 min, then alpha-chloro-4-methoxytoluene (0.074 mL, 0.547 mmol) was added. The reaction mixture was heated at 80° C. for 3 h. The reaction was quenched with sat'd NaHCO3 solution and extracted 3× with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (185 mg) as a red solid.