Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:30].O>C(Cl)Cl>[Br:30][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CCCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CCCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of {3-[(5-chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.75 mmol) in methylene chloride (4.8 mL) was added slowly a solution of boron tribromide in methylene chloride (3.8 mL, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. After methylene chloride layer was separated, water and EtOAc were added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (252 mg, 75%). LCMS for C20H21BrClN4O (M+H)+: m/z=447.0, 449.0. 1H NMR (400 MHz, CD3OD): δ 7.92 (s, 1H), 7.63 (s, 1H), 7.39 (s, 1H), 7.38 (m, 2H), 7.03 (t, J=7.2 Hz, 1H), 6.61 (m, 2H), 6.58 (s, 1H), 4.56 (s, 2H), 3.60 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 1.96 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:15]([C:24]1[CH:29]=[C:28]([C:30]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=1[OH:38])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[CH3:16].S(=O)(=O)(O)O.[N:44](OS(=O)(=O)O)=O>O>[N+:10]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:9]=[CH:8][C:6]=1[N:7]=[N:44][C:26]1[CH:27]=[C:28]([C:30]([CH3:31])([CH3:32])[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:29]=[C:24]([C:15]([CH3:17])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:16])[C:25]=1[OH:38])([O-:12])=[O:11]
Reactant: O=NOS(=O)(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 5 °C
Yield: 77 %

Procedure:
To a 1 L lab flask are added 54.6 g (0.26 mol, 99.9%) of 4-trifluoromethyl-2-nitroaniline, PETROSUL H-60 (5.3 g dissolved in 121.4 g water), 2-cumyl-4-tert-octylphenol (80.9 g, 0.25 mol, 92.5%) and ligroine (241.7 g, bp 90-110° C.). Sulfuric acid (32.7 g, 93%) is charged to the reactor with stirring. The reaction mass is cooled to 5° C. Nitrosylsulfuric acid (94.4 g, 0.30 mol, 40% in sulfuric acid) and water (84,5 g) are added via a peristaltic pump over 8 hours. The cooling bath is removed and the reaction mass is allowed to warm to room temperature overnight. The reaction mass is heated to 40° C. Stirring is stopped and the two phases separate. Removed the aqueous layer. The ligroine layer weighed 373.8 g and contained 25.73 weight % of desired product (96.2 g of monoazo corresponding to a yield of 77% based on phenol as determined by calibrated HPLC analysis). The product may be crystallized from hot methanol, resulting in a burgundy solid with a melting point of 101-105° C. as per co-pending application Ser. No. 09/632217 example 10. 1H-NMR (CDCl3; 499.8494 MHz): δ 0.85 (s, 9H); δ 1.42 (s, 6H); δ 1.77 (s, 2H); δ 1.78 (s, 6H); δ 7.14-7.30 (multiplet, 5H); δ 7.50 (d, 1H); δ 7.58 (d, 1H); δ 7.90 (d, 1H); δ 8.15 (d, 1H); δ 8.37 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]1([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:31]2[CH2:30][CH:29]=[C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33][CH2:32]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: C1=C(c2ccccc2)CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)C1
Yield: 77.9 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 16 mg of 4-phenyl-1, 2, 3, 6-tetrahydropyridine-hydrochloride, 0.013 mL of DIEA and 23 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 24 mg of the title compound. RF: 0.37 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ2.40-2.71 (m, 9H), 2.91-3.16 (m, 5H), 3.67 (ABq, J=13 Hz, 2H), 5.98-6.00 (m, 1H ), 7.07-7.41 (m, 15H). Mass Spectrum (ESI): 409.1 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.B1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH:32]=2)OC(C)(C)C(C)(C)O1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:31]3[CH:32]=[C:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][CH:36]=3)=[N:7][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CC1(C)OB(c2cccc(CC(N)=O)c2)OC1(C)C
Product: NC(=O)Cc1cccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)c1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 3-(2-Acetamidyl)phenylboronic acid pinacol ester using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]([NH2:14])[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.[N:17]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=2[N+:33]([O-:35])=[O:34])[CH2:22][CH2:21][O:20][CH2:19][C:18]1=[O:23]>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C:18]4=[O:23])=[C:25]([N+:33]([O-:35])=[O:34])[CH:26]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
237 mg (0.93 mmol) of (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine are dissolved with 0.257 ml TEA in 10 ml THF and a solution of 290 mg (1.02 mmol) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic acid chloride in 10 ml THF is added dropwise. The reaction mixture is stirred for 16 hours at ambient temperature and then evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->95:5).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:11]=[N:10][C:7]2=[CH:8][CH:9]=1>CCO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[CH2:11][NH:10][C:7]2=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Cl)cc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ccc(Cl)cc12
Reaction time: 8 h

Procedure:
NaBH4 (1.29 g, 34.0 mmol) was added to a stirred solution of tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate (2.57 g, 8.01 mmol) in absolute EtOH (100 mL) portionwise. The reaction was stirred at about room temperature overnight. The reaction was concentrated. The crude residue was taken up in DCM, washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (25-35% EtOAc/Hexane) to yield tert-butyl 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate. LCMS (APCI+) m/z 223, 225 [M+H−Boc]+; Rt=3.86 min.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8](C(O)=O)=[CH:7][CH:6]=1)=[O:4].C[N:16](C)[C:17](C1C=CC(C(N=[N+]=[N-])=O)=CC=1)=[O:18].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:43]=[C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[C:41]3=[CH:50][C:51]([CH2:53][N:54]([CH3:56])[CH3:55])=[CH:52][N:40]3[N:39]=2)=[CH:34][CH:33]=1>>[CH3:55][N:54]([CH2:53][C:51]1[CH:50]=[C:41]2[N:40]([CH:52]=1)[N:39]=[C:38]([C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:17](=[O:18])[NH:16][C:8]3[CH:7]=[CH:6][C:5]([C:3]([N:2]([CH3:1])[CH3:14])=[O:4])=[CH:13][CH:12]=3)=[CH:33][CH:34]=1)[N:43]=[C:42]2[N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)[CH3:56]
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Reactant: CN(C)C(=O)c1ccc(C(=O)N=[N+]=[N-])cc1
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)N(C)C)cc4)cc3)nn2c1
Yield: 25.8 %

Procedure:
According to the general method described in example 13, 4-(dimethylcarbamoyl)benzoic acid was used as starting material, and the resulting 4-(dimethylcarbamoyl)benzoyl azide reacted with 13a to give a light yellow solid (14 mg, 25.8%). m.p. 240° C. 1H NMR (300 MHz, DMSO-d6): δ 9.59 (s, 2H), 8.16 (d, J=8.5 Hz, 2H), 7.99 (s, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.19 (s, 1H), 4.25 (s, 2H), 4.08 (t, J=4.4 Hz, 4H), 3.80 (t, J=4.4 Hz, 4H), 2.96 (s, 6H), 2.69 (s, 6H). ESI-MS: 543 (4+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]([O:31][CH3:32])([CH3:30])[CH3:29])[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:32][O:31][C:28]([CH3:30])([CH3:29])[C:27]#[C:26][C:17]1[CH:18]=[C:19]2[C@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:9]3[C:10](=[CH:11][CH:12]=[C:7]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)[CH:8]=3)[O:13][C:14]2=[N:15][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 70 °C

Procedure:
A vial was charged with (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (104 mg, 0.210 mmol), pyridin-3-ylboronic acid (77 mg, 0.629 mmol), and tetrakis(triphenylphosphine)palladium (24.22 mg, 0.021 mmol). The vial was purged with Ar (g), then DMF (1048 μL) and potassium carbonate (524 μL, 1.048 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was capped and heated in a Biotage Initiator microwave reactor for 1.5 h at 70° C. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3-methoxy-3-methylbut-1-ynyl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[C:14]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C@H:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH3:48])[CH2:30]/[C:31](/[C:34]3[CH:39]=[CH:38][N+:37]([O-])=[C:36]([CH3:41])[CH:35]=3)=[N:32]\[OH:33])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)([OH:16])=[O:15].[OH-].[Na+]>ClCCl>[OH:33]/[N:32]=[C:31](/[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH2:41][OH:4])[CH:35]=1)\[CH2:30][C@H:29]([C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([C:14]([OH:16])=[O:15])[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]
Reactant: Cc1ccccc1[C@H](C/C(=N\O)c1cc[n+]([O-])c(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnc(CO)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Reaction time: 1 h
Yield: 13.7 %

Procedure:
Trifluoroacetic anhydride (421 mg, 2.01 mmol) was added at 0° C. to a suspension of (R,E)-4-(3-(4-(4-carboxypiperidin-1-yl)phenyl)-1-(hydroxyimino)-3-o-tolylpropyl)-2-methyl-pyridine 1-oxide (95 mg, 201 μmol) in dichloromethane (3 mL) to give a white suspension, then after 1 h another portion of trifluoroacetic anhydride (421 mg, 2.01 mmol) was added. The reaction mixture was allowed to reach room temperature over 1 h, then treated with 1 M aq. sodium hydroxide solution and stirred for another 90 min. After extraction with dichloromethane, the organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to produce the title compound (13 mg, 14%). Light yellow oil, MS (ESI+): m/z=474.4 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)C(C)C)(C)C.C(OCC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([Br:9])[CH:11]=2)[CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOCC
Product: Clc1cc(Nc2cccc(Br)c2)ncn1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of 4,6-dichloropyrimidine (5 g, 33.6 mmol), 3-bromoaniline (5.8 g, 33.7 mmol) and N,N-diisopropylethylamine (DIEA) (5.2 g, 40.2 mmol) in ethanol (40 mL) was heated at 80° C. for 16 hr. The reaction mixture was cooled to ambient temperature, diethylether (35 mL) was added while the mixture was being stirred. The product was precipitated, filtered, washed with water and dried to afford 5.9 g (62% yield) of a light colored solid. MS (m/z): MH+=284, 286, 288.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]([F:41])([F:40])[C:12]1[CH:13]=[C:14]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:16].O>ClCCl>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:14]([CH:13]=[C:12]([C:11]([F:10])([F:40])[F:41])[CH:35]=1)[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:19][C@H:18]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:16]
Reactant: O=C=NC1CCCCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CCCCC1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 4 h

Procedure:
Cyclohexyl isocyanate (0.06 ml) was added to a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.2 g) in dichloromethane (10 ml) at room temperature. After stirring for 4 hours, dichloromethane (10 ml) and water (5 ml) were added. The organic layer was separated, washed with brine and dried over magnesium sulfate. After evaporation of the solvent in vacuo,.the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-cyclohexylcarbamoyl-2-(1H-indol-3-yl-methyl)piperazine (0.18 g).
Reaction SMILES: O[Li].O.[CH3:4][CH:5]([CH3:24])[CH2:6][S:7]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)(=[O:9])=[O:8]>O.CO.C1COCC1>[CH3:4][CH:5]([CH3:24])[CH2:6][S:7]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)(=[O:8])=[O:9]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)CC(C)C)CC2
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CS(=O)(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Reaction time: 6 h

Procedure:
LiOH.H2O (200 mg, 4.8 mmol, 3 eq) in water (3 ml) was added dropwise to a cooled (0° C.) solution of (R)-methyl 3-(2-methylpropylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (C-03) (500 mg, 1.6 mmol, 1 eq) in MeOH:THF (1:1, 12 ml), and stirring was carried out for 6 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was taken up in water (50 ml), adjusted to pH 2 with 2M HCl solution and extracted with dichloromethane (2×80 ml). The combined organic phases were washed with sat. NaCl solution (40 ml), dried over sodium sulfate and concentrated and dried under reduced pressure. Yield: 450 mg
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH2:19]C)=[O:17].C(N(CC)CC)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:29]1([NH:28][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([O:1][C:16]([O:18][CH3:19])=[O:17])[C:7]=3[C:8]=2[CH3:14])=[O:13])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(C(=O)O)oc2cccc(O)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cccc2oc(C(=O)Nc3ccccc3)c(C)c12
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a mixture of 4-hydroxy-3-methylbenzofuran-2-carboxylic acid (1.12 g, 6 mmole), ethyl chloroformate (1.01 ml, 13.2 mmole), and methylene chloride (20 ml) stirred at 0°-5° C. under argon was added triethylamine (1.82 ml, 13.2 mmole) in methylene chloride (6 ml) dropwise over 5 minutes. The mixture was stirred for 15 minutes and then aniline (1.11 mg, 12 mmole) was added followed by the dropwise addition of triethylamine (1.82 ml, 13.2 mmole) in methylene chloride (3 ml). After 30 minutes, the reaction mixture was washed with water, dried with MgSO4 and evaporated to dryness. The crude product was purified by column chromatography (70 g of Merck silica gel eluted with 1:1:3 ethyl acetate/methylene chloride/hexane to yield 1.38 g (68.1%) of product.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=[O:42])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:41])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[S:32][C:33]3[CH:39]=[C:38]([OH:40])[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:25][CH:24]=1)([CH3:11])([CH3:10])[CH3:9].[NH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C1C[O:55][CH2:54]C1>>[C:8]([O:12][C:13](=[O:42])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:41])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:31]2[S:32][C:33]3[CH:39]=[C:38]([O:40][C:54](=[O:55])[NH:43][CH2:44][CH2:45][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:27][CH:28]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: NCCN1CCOCC1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(O)cc3s2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(OC(=O)NCCN4CCOCC4)cc3s2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
To a solution of p-nitrophenylchloroformate (171 mg, 0.848 mmol) in THF (15 mL) cooled to −78° C. under N2 atmosphere was added Et3N (236 μL, 1.70 mmol). Then a suspension of the intermediate 129 (416 mg, 0.848 mmol) in THF (4.2 mL) was added via canula. The resulting yellow mixture was stirred at −78° C. for 1 h and at 0° C. for 1.5 h, heated at 40° C. for 16 h and cooled to r.t. Then, neat 4-(2-aminoethyl)morpholine (119 μL, 0.848 mmol) was added and the solution was stirred for 4 h, quenched by addition of MeOH. It was allowed to stir for 30 min. and concentrated. The resulting material was purified by flash chromatography using MeOH/DCM (3:97) affording the title compound 132 (165 mg, 30% yield). 1H NMR: (DMSO-d6) δ (ppm): 9.77 (s, 1H), 8.64 (bs, 1H), 8.56 (t, J=5.9 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.60 (t, J=5.9 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.50-7.48 (m, 2H), 7.45 (d, J=2.3 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.90 (dd, J=8.2, 2.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 2H), 3.56 (t, J=4.1 Hz, 4H), 3.31 (t, J=6.1 Hz, 2H), 3.16 (q, J=6.1 Hz, 2H), 2.39 (t, J=6.8 Hz, 4H), 1.42 (s, 9H). m/z: 647.7 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=2)[CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:24][CH:23]=1.C(OCC)(=O)C>C(O)(C)(C)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[C:12]([S:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:26][CH:27]=3)[N:11]=[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=2)[CH:3]=1
Reactant: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Reactant: CCC(=O)Nc1ccc(S)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Sc2ccc(NC(=O)CC)cc2)n1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A suspension of Ethyl 2-(6-(5-methyl-1H-pyrazol-3-ylamino)-2-chloropyrimidin-4-yl)acetate (0.676 g, 2.29 mmol) and N-(4-mercaptophenyl)propionamide (0.415 g, 2.29 mmol) in t-butanol (10 ml) was heated under reflux overnight. Reaction mixture was then cooled to room temperature, ethyl acetate (20 ml) added causing precipitation of product. Solid was collected by filtration, washed with sat. sodium hydrogen carbonate solution, water, diethyl ether then dried by suction to leave title compound as a yellow solid (0.425 g, 43%). 1H NMR (DMSO) 1.12 (3H, t), 1.20 (3H, t), 2.00 (3H, s), 2.40 (2H, q), 3.66 (2H, s), 4.11 (2H, q), 5.05 (1H, br s), 5.30 (1H, br s), 7.53 (2H, d), 7.79 (2H, d), 10.20 (1H, s); ES+ 441.
Reaction SMILES: C(O[C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6]([OH:8])[CH3:7])C.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[CH3:7]/[C:6](/[OH:8])=[C:5](/[C:4]([NH:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:21])[F:22])=[CH:20][CH:19]=1)=[O:11])\[C:9]#[N:10]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(C#N)=C(C)O
Solvent: Cc1ccccc1C
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 70° C. to yield (62 g) of Teriflunomide.