Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.CN([C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)=[O:26])OC.[Cl-].[NH4+]>C1COCC1>[CH:8]([N:7]([CH2:6][C:5]1[CH:14]=[CH:15][C:2]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:31][CH2:32]2)=[O:26])=[CH:3][CH:4]=1)[CH:11]([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)N(Cc1ccc(Br)cc1)C(C)C
Reactant: CON(C)C(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)N(Cc1ccc(C(=O)C2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1)C(C)C
Reaction time: 0.5 h
Yield: 253.6 %

Procedure:
To a solution of N-(4-bromobenzyl)-N,N-diisopropylamine (2.3 g) in THF (10 ml) was added dropwise at −78° C. n-BuLi (1.6 mmol/ml hexane solution, 3.8 ml). Ten minutes later, N,O-dimethyl-N-(1-trityl-piperidine-4-carbonyl)hydroxylamine (1.5 g) in THF (20 ml) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to give the title compound (5.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([O:8][CH:9]([CH3:33])[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:19](=[O:32])[CH:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[CH3:21])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Ni]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:20]([CH3:21])[C:19]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:35][CH:34]=2)[CH3:33])=[O:32])=[CH:28][CH:27]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOCCOC(=O)C(C)Oc1ccc(N)cc1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
(4-Nitrophenoxy)-propionic acid 2-{2-[2-(4-nitrophenoxy)-propionyloxy]-ethoxy}-ethyl ester (300 g) was dissolved in ethyl acetate (1.5 L) in a pressure vessel. Raney Nickel catalyst (290 g) was added and the mixture was stirred under an atmosphere of hydrogen (10 Kg) for 4 hour. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure to obtain pure (4-aminophenoxy)-propionic acid 2-{2-[2-(4-aminophenoxy)-propionyloxy]-ethoxy}-ethyl ester (254 g) as a light yellow syrup. The product was characterized by 1H NMR (CDCl3) δ 1.60 (d, 3H, CH3), 3.20 (bs, 2H, NH2), 3.60 (t, 2H, CH2), 4.25 (t, 2H, CH2), 4.65 (q, 1H, CH), 6.60 (d, 2H, Ar), 6.75 (d, 2H, Ar).
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:7])[CH:5]=[C:4](/C(/C)=C/C2C=CSC=2)[O:3]1.C(S)[C@@H](O)[C@H](O)CS>>[CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:7])[CH:5]=[CH:4][O:3]1
Reactant: C/C(=C\c1ccsc1)C1=CC(=O)C(C)(c2ccccc2)O1
Agent: O[C@H](CS)[C@H](O)CS
Product: CC1(c2ccccc2)OC=CC1=O

Procedure:
According to the procedure of Method A, Example 1, 2-methyl-5-[(E)-1-methyl-2-thien-3-ylethenyl]-2-phenylfuran-3(2H)-one was reacted with 1,4-dithio-DL-threitol to provide 5-(2-{[(2S*3S*)-2,3-dihydroxy-4-mercaptobutyl]thio}-1-methyl-2-thien-3-ylethyl)-2-methyl-2-phenylfuran-3(2H)-one as a mixture of diastereomers: 1H NMR (CDCl3) δ1.45 (m, 1H), 1.50-1.65 and 1.75-1.80 (overlapped singlets and multiplets, ˜8H), 2.40-2.70 (m, ˜4H), 3.22 (m, 1H), 3.33-3.65 (m, 2H), 4.33 (m, 1H), 5.25-5.52 (overlapped singlets, 1H), 7.05-7.60 (m, 8H); MS (HR-FAB) m/z 451.1116 (M+H calcd. for C22H27O4S3 451.1072).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[C:19]([NH:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[CH3:27][C:22]([NH:21][C:19]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:20])([CH3:26])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(NC(=O)c1ccc2ccccc2c1C#Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1CCc1ccccc1)C(=O)O
Reaction time: 14 h
Yield: 18.6 %

Procedure:
17 mg 2-{[1-(phenylethynyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid were dissolved in 4 ml of MeOH, 19 mg 10% Pd on charcoal were added and the mixture hydrogenated at room temperature for 14 h. Filtration, RP-HPLC and freeze-drying gave 3.2 mg of 2-Methyl-2-[(1-phenethyl-naphthalene-2-carbonyl)-amino]-propionic acid (18%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:10]([NH:27][C:28]3[N:36]=[CH:35][N:34]=[C:33]4[C:29]=3[N:30]=[CH:31][NH:32]4)[CH2:9][OH:8])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:14]=2[CH:22]=1
Reactant: Fc1ccc2nc([C@H](COCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccn3)c2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: OC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl](7H-purin-6-yl)amine (336 mg, 0.7 mmol) in anhydrous DCM (8 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron tribromide (1.0M in DCM, 2.6 mL, 2.6 mmol). The reaction mixture was stirred at 0° C. for 1 h. MeOH was added and the volatiles removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 280 as a white solid (225 mg, 82%). LCMS (Method K): RT 2.72 min [M+H]+ 391.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, br s), 8.68 (1H, s), 8.20-8.08 (2H, m), 8.03 (1H, s), 7.85 (1H, d, J=7.87 Hz), 7.71 (1H, dd, J=8.80, 4.89 Hz), 7.57 (1H, t, J=6.07 Hz), 7.30-7.06 (3H, m), 5.84 (1H, s), 5.11 (1H, s), 4.01-3.82 (2H, m)
Reaction SMILES: [NH2:1][CH2:2]CNC1N=CC(C#N)=CC=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+]([O-])=O)=[CH:33][N:32]=2)[CH:24]=[CH:23][C:22]=1[C:40]1[NH:41][CH:42]=[CH:43][N:44]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[N:32]=[CH:33][C:34]([C:2]#[N:1])=[CH:35][CH:36]=2)[CH:24]=[CH:23][C:22]=1[C:40]1[NH:44][CH:43]=[CH:42][N:41]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: N#Cc1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[6-(2,4-dichlorophenyl)-5-imidazol-2-yl-2-pyridyl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile using the general method for [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:18])=[O:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>FC(F)(F)C(O)=O.O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][S:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[N+:1]([O-:4])=[O:2])(=[O:17])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCS(=O)(=O)CCOCCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCS(=O)(=O)CCOCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated nitric acid (3.25 ml) was added dropwise over a half hour period to a stirred cooled (ice/salt) solution of methyl 3-[2-[2-phenylethoxy]ethylsulphonyl]propanoate (15.12 g) (prepared from the acid, which was itself prepared by the procedure outlined in Example 1b)) in trifluoroacetic acid. The reaction was allowed to warm to room temperature, stirred overnight, diluted with water and extracted several times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to yield the crude mixture of isomeric methyl 3-[2-[2-[nitrophenyl]ethoxy]ethylsulphonyl propanoates. The subtitled compound was separated from the other isomers by normal phase preparative HPLC using 1:1 hexane:ethyl acetate as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([O:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH:12]=1)=[O:5].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([O:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH:12]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(COC(=O)c3ccccc3Cl)nn2)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: O=C(OCc1cn(C2CCNCC2OCc2ccc3ccccc3c2)nn1)c1ccccc1Cl

Procedure:
In an analogous manner to that described in Example 136(a), from tert-butyl (3RS,4RS)-4-[4-(2-chloro-benzoyloxymethyl)-[1,2,3]triazol-1-yl]-3-(naphthalen-2ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group with hydrogen chloride in methanol there was obtained 1-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-1H-[1,2,3]triazol-4-ylmethyl 2-chloro-benzoate hydrochloride (1:1) in the form of colourless crystals; MS: 477 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1.IC1C2C(=CC(C#N)=CC=2)NN1C.C([Mg]Cl)(C)C.Cl[Sn:33]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[CH3:13][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]([Sn:33]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:34][CH2:35][CH2:36][CH3:37])=[N:3]1
Reactant: Cn1nc(I)c2ccc(C#N)cc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: CN1Nc2cc(C#N)ccc2C1I
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C#N)ccc12
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
The crude mixture of 3-iodo-1-methyl-1H-indazole-6-carbonitrile and 3-iodo-2-methyl-1H-indazole-6-carbonitrile (97 mg, crude) was dissolved in THF (4 mL). The solution was cooled to −40° C. Isopropylmagnesium chloride (0.21 mL, 0.41 mmol, 2M in THF) was added drop-wise at −40° C. The reaction mixture was stirred at −40° C. for 20 min. Then chlorotributyltin (0.11 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with EtOAc (3×5 mL), organics were washed with water (10 mL), brine (2×10 mL) and dried over Na2SO4 and concentrated. The residue was used to the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=[O:4].CC(N1[C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])=[CH:15][C:14]([CH3:50])=N1)(C)C.CC(N1C(C(NCC2C=CC(B(O)O)=CC=2)=O)=CC(C)=N1)(C)C>>[CH2:48]([S:45]([N:42]1[CH2:41][CH2:40][CH:39]([C:30]2[C:29]3[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17]([C:16]5[O:4][CH:50]=[CH:14][CH:15]=5)=[O:18])=[CH:22][CH:23]=4)[CH:28]=3)[NH:32][CH:31]=2)[CH2:44][CH2:43]1)(=[O:47])=[O:46])[CH3:49]
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5cc(C)nn5C(C)(C)C)cc4)cc23)CC1
Agent: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5ccco5)cc4)cc23)CC1
Yield: 25 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (4-{[(2-furanylcarbonyl)amino]methyl}phenyl)boronic acid (118 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 16 mg of the title compound (25%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:19]3[CH2:20][CH2:21][C:16]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:17][CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: OC1CCC2(CC1)OCCO2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(I)cn2C1CCC2(CC1)OCCO2
Reaction time: 20 h
Yield: 200.8 %

Procedure:
To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.09 mol), 1,4-dioxaspiro[4.5]decan-8-ol (35.8 g, 0.0267 mol) and triphenylphosphine (46.7 g, 0.178 mol) in THF (1.2 L) was added diethylazodicarboxylate (30.9 g, 0.178 mol) under nitrogen. The solution was stirred for 20 hr and the majority of solvent was then evaporated (250 mL remaining). EtOAc (450 mL) was then added and the resulting solid was filtered, washed with EtOAc (2×50 mL) and dried in vacuo to give 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (22.5 g, 60%) as a cream solid. 1H NMR (d6 DMSO, 400 MHz) 8.64(1H, s), 8.10(1H, s), 4.74(1H, m), 3.90(4H, m), 2.12(2H, m), 1.91(2H, m), 1,71-1.83(4H, m). Rf in 1:4 EtOAc:heptane=0.12.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(O)c1ccsc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
2-bromo-3-thiophene carboxylic acid (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH2Cl2 (200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98% yield) as a crude brown oil. LCMS (ES): 99% pure, m/z not detected;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:11][S:12](O)(=[O:14])=[O:13].O=S(=O)=O>O>[N+:1]([C:4]1[CH:9]=[C:8]([S:12]([OH:14])(=[O:13])=[O:11])[C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reaction time: 2.8 h
Yield: 99.15 %

Procedure:
After 2.8 hours of operation, the cascade reaction train was shut down, including 4-nitrotoluene, oleum, and water flows. The molten sulfonation mass in the first three reactors was allowed to solidify. Several days later, the reactors were heated to about 105°-115° C. The reactant feeds were restarted using oleum with an 82.7% free SO3 assay. The 4-nitrotoluene and oleum flows were set at 4.18 g/min and 3.4 g/min (SO3 excess 15%). The water flow to the fourth cascade vessel was started at 13.9 g/min. After operating the systems for five hours, samples were taken from the first three reactors and analyzed. The conversion in R-1, R-2 and R-3 were 97.0, 99.4, and 99.98 respectively. After 5.8 hours running, samples were again taken and analyzed. Conversion was 97.4% in the first reactor, 99.4% in the second and 100% in the third. The final sample collected at the overflow from the dilution vessel (#4 ) for 68 minutes showed 4-nitrotoluene conversion to be 99.7% with a yield of 99.15% of 4-nitrotoluene-2-sulfonic acid. 0.73% of theory yield was lost to sulfone formation. The final solution contained only 0.02% of unreacted 4-nitrotoluene and 16% sulfuric acid relative to 4-nitrotoluene-2-sulfonic acid. The dilute 30% 4-nitrotoluene-2-sulfonic acid solution is ready for use in other processes without any further treatment.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[ClH:45]>C(Cl)Cl.O1CCOCC1>[ClH:45].[ClH:45].[ClH:45].[O:1]([C:8]1[C:9]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-butyl 4-(5-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (10 g, 16 mmol) was dissolved in 1:1 CH2Cl2:methanol and 4N HCl in dioxane was added (80 mL). The reaction was stirred for 1 hour and then concentrated in vacuo to afford 3-phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (10 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH2:28][CH2:27][CH2:26][CH:25]=3)[C:5]2=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(C2=CCCC2)N1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(C2CCCC2)N1
Yield: 31.4 %

Procedure:
In a manner similar to the method described in example 72, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(cyclopent-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.23 mmol) prepared in example 77c was treated with platinum oxide in ethyl acetate under hydrogen (50 psi) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.031 g, 31%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:17]([NH2:19])=O.CN(C=O)C>C(O)=O>[CH2:15]([O:14][C:12]([C:4]1[NH:3][C:2]2[N:1]=[CH:17][N:19]=[C:7]([OH:8])[C:6]=2[CH:5]=1)=[O:13])[CH3:16]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(N)[nH]1
Solvent: O=CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(O)ncnc2[nH]1
Temperature: 2.5 °C

Procedure:
With the exclusion of air, 51.5 g (227 mmol) of 2-amino-3,5-bis(ethoxycarbonyl)-1H-pyrrole, 455 ml of formamide, 227 ml of DMF and 113 ml of formic acid are stirred at 140° C. for 27 hours. The resulting yellow suspension is cooled to 0-5° C. Filtering and washing with isopropanol and hexane yield the title compound; 1H-NMR (DMSO-d6): 13-12 (2 HX), 7.99 and 7.11 (2s, 2H), 4.31 (q, J=7, 2H), 1.32 (t, J=7, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19]C5CCCC=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[CH2:40][CH2:41][CH2:42][CH3:43]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:40]([CH2:41][CH2:42][CH3:43])=[C:39]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: CCCCC(=O)c1ccccc1
Product: CCCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert valerophenone (0.488 g, 3.01 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.6-11.8 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-phenyl-5-propyl-1,3-thiazol-2-amine as a yellow powder (0.135 g, 0.222 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 10.08 min;
Reaction SMILES: C[O-].[Na+:3].[F:4][C:5]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:6]=1[CH2:7][N:8]1[N:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22].C(O)(C)C>CO>[F:4][C:5]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:6]=1[CH2:7][N:8]1[N:17]=[C:16]([CH2:18][C:19]([O-:21])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22].[Na+:3]
Reactant: O=C(O)Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: O=C([O-])Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2ccccc12
Temperature: 25 °C

Procedure:
A solution of sodium methoxide (25 ml. of a 1.0 M solution in methanol) was added to a solution of 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (9.87 g.) in methanol (300 ml.) and the mixture heated to its boling point. Methanol was then allowed to boil off until the volume of the mixture was approximately 100 ml. Isopropanol (150 ml.) was then added, followed by petrol (60-80) until the mixture was just opaque. The mixture was then allowed to cool to room temperature. The solid which formed was separated by filtration, evaporated with toluene (2×400 ml.) and then washed with ether (300 ml.) to give sodium 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate, 6.5 g., m.p. 244°-247° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:21]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[CH3:19])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ccsc2n1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Cl)nc3sccc23)c(C)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (805 mg, 3.94 mmol), TFA (0.91 mL, 11.82 mmol) in TFE (11 mL) was added 2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. The reaction was stirred at 90° C. for 2 d. Reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC to afford the product as a white solid (43.4 mg, 36%):