Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19](O)=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)[CH:15]=2)=[CH:10][CH:9]=1.[CH3:32][N:33]([CH:35]=O)[CH3:34].C(N(CC)CC)C.Cl.[CH3:45][NH:46][O:47][CH3:48]>ClCCl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]([N:46]([O:47][CH3:48])[CH3:45])=[O:20])=[C:16]([C:22]3[CH:23]=[CH:24][C:25]([S:28](=[O:31])(=[O:30])[N:29]=[CH:35][N:33]([CH3:32])[CH3:34])=[CH:26][CH:27]=3)[CH:15]=2)=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)sc2C(=O)O)cc1
Reactant: CNOC
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
Oxalyl chloride (0.70 g, 0.48 ml, 5.58 mmol) was added drop wise at 0° C. to a solution of 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 33c, 1.10 g, 2.79 mmol) in a mixture of dichloromethane (30 ml) and DMF (0.40 g, 0.43 ml, 5.58 mmol). The mixture was then allowed to warm to room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (30 ml) and the mixture was then cooled to 0° C. To the cooled mixture was added triethylamine (1.69 g, 2.32 ml, 16.75 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.58 mmol) under stirring. The reaction mixture was then stirred at room temperature for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (25 ml) and washed with water (2×25 ml) and organic layer so obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by flash column chromatography using 0.8% methanol in DCM as an eluent to obtain the title compound (0.9 g, 65.69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Br[CH2:32][CH2:33][CH2:34]C(Cl)=O.[H-].[Na+].CC(N(C)C)=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][C:30]4=[O:42])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(Cl)CCCBr
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 1 h
Yield: 9 %

Procedure:
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-[2-(methylamino)ethoxy]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 24/50 mg, 0.12 mmol) was dissolved in DMA (1 ml) and 4-bromobutyryl chloride (14 μl, 0.12 mmol) was added drop-wise at −15° C. After 1 hour at room temperature, sodium hydride (60%, 29 mg) was added to the mixture and stirring was continued for 3 hours. The reaction was quenched with water and the crude product was purified by preparative HPLC (column beta-basic, Hypercil 5 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (5 mg, 9%); NMR Spectrum: 1.90-1.95 (m, 2H), 2.25 (t, 2H), 3.47 (t, 2H), 3.68 (br s, 2H), 4.39 (br s, 2H), 5.28 (s, 2H), 7.25 (d, 1H), 7.36 (t, 1H), 7.57 (d, 1H), 7.80-7.89 (m, 2H), 8.16 (br s, 2H), 8.32 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 480 (MH+).
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd]>[C:20]1([NH:19][C:17]2[N:16]=[CH:15][C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCc3cnc(Nc4ccccc4)nc3CC2)cc1
Agent: [Pd]
Product: c1ccc(Nc2ncc3c(n2)CCNCC3)cc1
Yield: 77 %

Procedure:
150 mg (7-benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-phenyl-amine and 20 mg palladium on charcoal in 10 mL was stirred 1 day under 3 bar of a hydrogen atmosphere. The mixture was filtered and evaporated to yield 84 mg of the desired product. (M+H)+=241
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)[C:20]1[C:19]([OH:18])=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1O
Reactant: Oc1cccc2cccnc12
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(NC(c2ccccc2O)c2ccc3cccnc3c2O)n1

Procedure:
The title compound was prepared by method B presented for the compound of Example 1 with the change that the reaction was conducted with salicylaldehyde (Molar), 2-amino-6-picoline (1 equivalent) and 8-hydroxy-quinoline (0.6 equivalent) as starting materials. Product precipitation; C22H19N3O2; (MW: 357.1), yield 1.6 g, (50.9%); m.p.: 189-191° C.; HPLC (CH3CN/H2O 70.30 Phenomenex C18 282 nm): Tr=5.05 min. 1H NMR 13 (DMSO) δ 2.23 (3H, s), 6.34 1H, d, J=6.0 Hz), 6.38 (1H, d, J=7.1 Hz), 6.69 (1H, t, J=7.2 Hz), 6.80 (2H, m) 7.02 (2H, m), 7.18 (1H, d, J=6.2 Hz), 7.25 (1H, d, J=6.8 Hz), 7.36 (1H, d, J=7.4 Hz), 7.42-7.54 (1H, m), 7.64 (1H, d, J=7.9 Hz), 8.25 (1H, d, J=7.1 Hz), 8.80 (1H, s), 9.85 (1H, s) —C NMR 13 (DMSO) δ 23.9 (CH3), 47.8 (CHNH), 111.1 (CH), 115.7 (CH), 116.7 (CH), 118.7 (CH), 121.5 (CH), 125.3 (Cq), 127.2 (CH), 127.4 (Cq), 127.8 (CH), 128.3 (CH), 129.2 (Cq), 135.9 (CH), 137.5 (CH), 138.2 (Cq), 148.1 (CH), 149.7, 155.1, 155.6 and 157.6 (4×Cq).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][N:15]=[C:16]=[S:17]>>[CH3:14][NH:15][C:16](=[S:17])[NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: CN=C=S
Reactant: NC1=NN(c2ccc(Cl)cc2)CC1
Product: CNC(=S)NC1=NN(c2ccc(Cl)cc2)CC1

Procedure:
3-Amino-1-(4-chlorophenyl)-2-pyrazoline (1.5 g) (prepared in Reference Example 6 of our European patent specification No. 22-578) and methylisothiocyanate (1.02 g) were heated together at 100° for two hours. The crude product was ground under methanol, collected by filtration, and recrystallised from acetone to yield 3-(3-methylthioureido)-1-(4-chlorophenyl)-2-pyrazoline, m.p. 237°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([OH:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].COC1C=C(C2C=CC(N)=C(OC)C=2)C=CC=1N.I.[CH3:36][Si:37]([CH3:40])([CH3:39])Cl>O1CCCC1.C(N(CC)CC)C>[CH3:36][Si:37]([CH3:40])([CH3:39])[O:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][Si:37]([CH3:40])([CH3:39])[CH3:36])=[C:11]([O:16][Si:37]([CH3:40])([CH3:39])[CH3:36])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH:8][Si:37]([CH3:40])([CH3:39])[CH3:36]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc(-c2ccc(N)c(O)c2)cc1O
Agent: COc1cc(-c2ccc(N)c(OC)c2)ccc1N
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)Nc1ccc(-c2ccc(N[Si](C)(C)C)c(O[Si](C)(C)C)c2)cc1O[Si](C)(C)C

Procedure:
0.540 g of 3,3'-dihydroxy-4,4'-diaminobiphenyl (synthesized from 3,3'-dimethoxy-4,4'-diaminobiphenyl using hydrogen iodide by the known method) and 1.52 g of triethylamine were dissolved in 16 mL of dry tetrahydrofuran. 1.63 g of trimethylchlorosilane was then added dropwise followed by heating under reflux for 72 hours. Operating in an argon atmosphere, the salt was filtered off and the solvent, etc., was removed under reduced pressure to yield 3,3'-bis(trimethylsiloxy)-4,4'-bis(trimethylsilylamino)biphenyl.
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:10]([N-]C(C)C)([CH3:12])[CH3:11].[Li+].ICCC>C1COCC1.CS(C)=O>[CH2:8]([O:7][C:5]([C:1]1([CH2:11][CH2:10][CH3:12])[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:9]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCCI
Product: CCCC1(C(=O)OCC)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Ethyl cyclobutanecarboxylate 1 (25.0 g, 0.195 mol) was added to a solution of lithium diisopropylamide (97.5 mL of a 2.0M solution in THF, 0.195 mol) in THF (200 mL) at −78° C. After 30 min the reaction solution was warmed to room temperature and transferred via cannula to a solution of 1-iodopropane (49.7 g, 0.293 mol) in DMSO (104 mL) while maintaining the temperature between 15-20° C. After stirring for an additional 30 min the precipitated salts were removed by vacuum filtration. The filtrate was concentrated in vacuo, diluted with hexane and washed with 1 N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by vacuum distillation (105-108° C., 20-30 mmHg) to give 16 g (48%) of the ester 2 as a clear, colorless oil.
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].CCOC(C)=O.[CH2:22]([OH:27])[C:23]([F:26])([F:25])[F:24]>O1C=CC=C1>[CH3:14][C:2]([O:27][CH2:22][C:23]([F:26])([F:25])[F:24])([CH3:15])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: OCC(F)(F)F
Reactant: CC(C)(Br)C(=O)NOCc1ccccc1
Solvent: c1ccoc1
Solvent: CCOC(C)=O
Product: CC(C)(OCC(F)(F)F)C(=O)NOCc1ccccc1

Procedure:
Produced as a by-product 56% from the reaction of 2-bromo-2-methyl-N-(phenylmethoxy)propanamide with TEA in furan and trifluoroethanol. Rf=0.26 (3:1, hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 7.56-7.31 (m, 5H), 4.94 (s, 2H), 3.68 (q, J=8.3 Hz, 2H), 1.43 (s, 6H); 13C NMR (125 MHz, CDCl3) 13C NMR (101 MHz, cdcl3) δ 170.8, 134.9, 129.4, 129.0, 128.7, 123.7 (q, J=278 Hz), 80.4, 78.3, 61.6 (q, J=35 Hz), and 23.6; FT-IR 3218 (br), 3036; 2942, 2886, 1663 (st), 1430, 1455, 1485, 1386, 1369, 1307, 1285, 1217, 1181, 1145, 1029, 1010 cm-1; HR-ESIMS calculated for C13H17F3NO3 (M+H)+ 292.1155, observed 292.1160.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH:13]([N:26]1[CH2:29][CH:28]([CH2:30]OS(C)(=O)=O)[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH:13]([N:26]1[CH2:29][CH:28]([CH2:30][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([F:3])[CH:12]=3)[CH:8]=[CH:9]2)[CH2:27]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2ccn(CC3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a suspension of sodium hydride (60% mineral oil dispersion, 0.19 g, 4.6 mmol) in anhydrous DMF (20 mL) was added 6-fluoroindole (0.65 g, 2.6 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then a solution of methanesulfonic acid 1-benzhydryl-azetidine-3-ylmethyl ester (0.78 g, 2.3 mmol) in DMF was introduced at 0° C. The resulting mixture heated at 60° C. for 16 hours. The reaction was quenched with water and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (10–30% ethyl acetate-hexane). The product-containing fractions were concentrated under vacuum to give 0.60 g (52%) of the title compound as a light brown oil. MS ES m/e 371 (M+H)+; 1H NMR (500 MHz, DMSO-D6): 2.76–2.79 δ (m, 3H), 3.05–3.07 δ (m, 2H), 4.29–4.31 δ (m, 3H), 6.37 δ (m, 1H), 6.78–6.83 δ (m, 1H), 7.09–7.13 δ (m, 2H), 7.18–7.22 δ (m, 4H), 7.31–7.35 δ (m, 6H), 7.46 δ (m, 1 H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][C:15]1([NH2:18])[CH2:17][CH2:16]1>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:18][C:15]3([CH3:14])[CH2:17][CH2:16]3)[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC1(N)CC1
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CC1
Yield: 25.6 %

Procedure:
A solution of 3,6-dichloro4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (386 mg, 1.5 mmol) in 1-methylcyclopropylamine (1.0 g, 14 mmol) was stirred for 24 h at 85° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with ethyl acetate (1-2 ml) and filtered. The white precipitate was stirred in 4M hydrochloric acid (5 ml) for 2 h and then filtered off and chromatographed on silica gel with ethyl acetate to give 112 mg (26%) of the pure title compound; mp 251-252° C. dec; 1H-NMR (DMSO-d6): δ0.65-0.79 (m, 4H), 1.36 (s, 3H), 7.11 (s, 1H), 7.82 (br s, 1H), 10.78 (br s, 1H); MS: m/e 291/293 (M+); (C9H10N3Cl1O2S2) calc. C, 37.05; H, 3.45; N, 14.40; found C, 36.96; H, 3.53; N, 14.15.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:24][F:25])([CH2:22][F:23])[CH:9]=1)=O)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.C1C=CC=CC=1>C(Cl)Cl>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:24][F:25])([CH2:22][F:23])[CH:9]=1)=[S:35])#[N:2]
Reactant: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: N#CCCNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 80 °C
Yield: 89.6 %

Procedure:
A mixture of 92 mg of N-(2-cyanoethyl)-2,2-bisfluoromethyl-6-trifluorometyl-2H-1-benzopyran-4-carbamide, 60 mg of Lawesson's reagent and 2 ml of benzene was stirred with heating at 80° C. for one hour. The reaction mixture was subjected to silica gel column chromatography (eluent:methylene chloride) to give 50 mg of N-(2-cyanoethyl)-2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carbothioamide; m.p. 105-106° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2cc(Cl)ncn2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cc(-c3ccc(OC(F)(F)F)cc3)ncn2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid. 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 9.38 (d, J=0.9 Hz, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.23 (d, J=8.5 Hz, 2H), 8.16 (d, J=0.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H); EIMS 344 m/z (M+).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:26][CH2:25][CH2:24][N:23]([C:27](=[O:48])[C@@H:28]([C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=5)[CH2:29][N:30](C(OC(C)(C)C)=O)[CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:21]4)[C:14]=3[C@H:13]([CH3:49])[CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[Li+]>C1COCC1.O.CCOC(C)=O>[ClH:47].[ClH:47].[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C@@H:28]([CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])[C:27]([N:23]2[CH2:24][CH2:25][CH2:26][N:20]([C:19]3[C:14]4[C@H:13]([CH3:49])[CH2:12][C@@H:11]([OH:10])[C:15]=4[N:16]=[CH:17][N:18]=3)[CH2:21][CH2:22]2)=[O:48])=[CH:42][CH:43]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCCN(c2ncnc3c2[C@H](C)C[C@H]3OC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)NC[C@@H](C(=O)N1CCCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Product: Cl
Reaction time: 16 h
Yield: 231.4 %

Procedure:
(5R,7R)-4-(4-((S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoyl)-1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (50 mg, 0.069 mmol) was dissolved in a THF/water mixture (1:1, 2 mL), and then solid lithium hydroxide (6 mg, 0.139 mmol) was added. The resultant mixture was stirred at ambient for 16 hours, at which time it was diluted with EtOAc and then washed twice with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting residue was taken up in dichloromethane (5 mL), and then HCl (4M in dioxane, 0.25 mL) was added. The mixture was stirred for 16 hours, at which time solvents were removed via rotary evaporation. The resulting residue was dissolved in dichloromethane (1 mL) and then added to diethyl ether (50 mL). The resulting precipitate was collected by filtration and dried to give (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (29 mg, 78%). LCMS (APCI+) M+=472.2, Rt=2.05 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27]C=CN=1)C1C=CC=CC=1.C([O-])=O.[NH4+:32].[CH2:33](O)[CH3:34]>[Pd]>[N:32]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:34][CH:33]=1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccccn3)C2)cc1
Reactant: CCO
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Product: c1cc(CC[C@H]2CNCCN2)ccn1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-(2-pyridinyl-ethyl)-piperazine (2.14 g, 5.76 mmol) in ethanol (40 mL). Add ammonium formate (2.18 g, 34.6 mmol) and palladium (430 mg, 5 wt. % on carbon) and heat to reflux. After 6 hours 30 minutes, filter the palladium on carbon and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (5%–15%) as the eluent to give 945 mg (86%) of the title compound: mp 113–116° C.; mass spectrum (ion spray): m/z=192 (M+1). Analysis calculated for C11H17N3: C, 69.07; H, 8.96; N, 21.97. Found: C, 69.08; H, 8.77; N, 21.81.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:17][S:16]2(=[O:29])=[O:28])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:17]([CH3:1])[S:16]2(=[O:28])=[O:29])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C(Cc2ccccc2)NS(=O)(=O)N1CSc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(Cc2ccccc2)C(=O)N(CSc2ccccc2)S1(=O)=O
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Potassium t-butoxide (5.65 g, 50.35 mmol) was added to a solution of 2-phenylthiomethyl-4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (14.61 g, 41.93 mmol) in 250 ml of THF at 0° C. and the mixture was stirred at this temperature for 1/2 hour. To the above mixture was added methyl iodide (35.69 g, 251.58 mmol) at 0° C. and the resulting mixture was allowed to stir for 4.5 hours at room temperature. The resulting mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 12.53 g (82.4%) of 2-phenylthiomethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide as a yellow solid.
Reaction SMILES: [S:1]([CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8])([OH:4])(=[O:3])=[O:2].[NH3:11]>>[S:1]([CH2:5][CH2:6][S:7]([O-:10])(=[O:9])=[O:8])([O-:4])(=[O:3])=[O:2].[NH4+:11].[NH4+:11]
Reactant: N
Reactant: O=S(=O)(O)CCS(=O)(=O)O
Product: O=S(=O)([O-])CCS(=O)(=O)[O-]
Product: [NH4+]

Procedure:
In the first preferred embodiment of the present invention, ethionic acid is reacted with an aqueous solution of excess ammonia to afford ammonium ethionate. The molar ratio of ammonia to ethionic acid can be in the range of 5 to 15, more preferably in the range of 8 to 10. Too little ammonia increases the formation of ditaurine, a byproduct, while more ammonia is desirable for the reaction, too much ammonia increases the process cost in the recovery of excess ammonia. The reactions are described as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=2)=[C:18]([Cl:34])[CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:33]=[CH:32][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=3)=[C:18]([Cl:34])[CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)c(Cl)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)c(Cl)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A solution of 205 mg (0.926 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 10 min. to a solution of 273 mg (0.926 mmol) 3-[4-(4-amino-2-chloro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 3 ml THF and stirring continued overnight. The reaction mixture was evaporated and purified by chromatography on silica (dichloromethane/ethanol 97:3). The obtained material was stirred with dichloromethane. The precipitate was filtered and dried to yield 130 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]2[O:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(O)c(N)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: COc1ccc2oc(-c3ccc(F)cc3)nc2c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-4-methoxyphenol (3.07 g, 22.09 mmol) and 4-fluorobenzaldehyde (3.55 mL, 33.14 mmol) in 40 mL of methanol was stirred at 45° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methylene chloride (50 mL), to which was added DDQ (6.02 g, 26.51 mmol) slowly. The resulting mixture was stirred at room temperature for 45 minutes. The solvent was evaporated under reduced pressure, and to the residue was added 300 mL of ethyl acetate. The organic layer was washed sequentially with saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated under reduced pressure. Column chromatography (ethyl acetate:Hexanes=1:9) gave 2-(4-fluorophenyl)-5-methoxybenzoxazole as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 105.7 %

Procedure:
To 3-[2-(4-Amino-1-piperidyl)ethyl]indole (1.307 g.) suspended in a solution of triethylamine (2 mls.) in dichloromethane (10 mls.) at room temperature with stirring was added methane sulphonyl chloride (0.570 g.) in dichloromethane (5 mls.). After stirring for 18 hours the solution was washed with water and the organic phase separated, dried and evaporated to yield the title compound (1.690 g.) as an oil. This was recrystallized from ethanolic hydrogen chloride as the hydrochloride salt (0.560 g., m.p. 241°-242° C.).