Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[NH:11])[NH2:10])[CH2:5][CH2:4]1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([OH:2])[CH2:4][CH2:5]2)[N:11]=1
Reactant: N=C(N)N1CCC(O)CC1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OC1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carboximidamide hydrochloride (1.80 g, 10.0 mmol) and perchloromethyl mercaptan (2.15 ml, 20.0 mmol) in dichloromethane (50 ml) was added dropwise a solution of sodium hydroxide (3.20 g, 80.0 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 350 mg (12.7%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])=[CH:4][CH:3]=1.S(Cl)[Cl:13]>[Fe](Cl)(Cl)Cl>[Cl:13][C:7]1[CH:6]=[C:5]([C:8]([Cl:9])([Cl:10])[Cl:11])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reactant: ClSCl
Agent: Cl[Fe](Cl)Cl
Product: Clc1ccc(C(Cl)(Cl)Cl)cc1Cl
Temperature: 80 °C
Yield: 51.4 %

Procedure:
A mixture of 57.5 g (250 mmol) of p-chlorobenzotrichloride, 1.5 g (9.2 mmol) of iron(III) chloride and 28 g (272 mmol) of sulphur dichloride was warmed to 80° C. for 3 hours. Thereafter, it was worked up in the manner indicated in Example 1. 34 g of 3,4-dichlorobenzotrichloride were thus obtained.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([NH2:42])=[C:37]([NH2:43])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1.[CH3:48][C:49](O)=O>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]4[NH:42][C:48]([CH3:49])=[N:43][C:37]=4[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1
Reactant: CC(=O)O
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N
Product: Cc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCN(C)CC4)CC3)cc(C)c2[nH]1

Procedure:
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were refluxed in 2 mL AcOH for 2 h and then evaporated down i.vac. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[CH:9]3)=[CH:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH2:10][CH2:9]3)=[CH:2]1
Reactant: c1cc2cc(-c3ccsc3)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: c1cc(-c2ccc3c(c2)CCN3)cs1
Yield: 100 %

Procedure:
5-(3-Thienyl)indole D40 was reduced in the usual way with sodium cyano borohydride in glacial acetic acid to give the title compound (D41) (1.0 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]=[N:9][OH:10])[CH2:3]1.[CH2:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])[CH:12]=[CH2:13]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH2:13][CH:12]([CH2:11][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[O:10][N:9]=2)[CH2:3]1
Reactant: C=CCN1CCCC1=O
Reactant: CN1CCCC(C=NO)C1
Product: CN1CCCC(C2=NOC(CN3CCCC3=O)C2)C1
Yield: 41.1 %

Procedure:
The desired compound was prepared by the method of Example 8 from 300 mg (2.11 mmol) of 1-methyl-piperidin-3-carbaldehyde oxime prepared in Example 5 and 528 mg (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6 and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 10:1) as eluent to obtain 230.1 mg (41% yield) of 1-[3-(1-methyl-piperidin-3-yl)-4,5-dihydro-isoxazol-5-yl-methyl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([F:11])[CH:4]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[F:11][C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(F)cc(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)cc(CC#N)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
To a solution of 1-(chloromethyl)-3-fluoro-5-methoxybenzene (2.9 g, 17 mmol) in DMSO (20 mL), a solution of KCN (2.2 g, 34 mmol) and KI (5.6 g, 34 mmol) in H2O (10 mL) was added. The mixture was stirred at 45° C. for 6 h, poured into H2O (20 mL), and extracted with DCM (3×30 mL). The organic phase was washed with brine (2×10 mL), dried over Na2SO4, and concentrated to give 2.62 g of 2-(3-fluoro-5-methoxyphenyl)acetonitrile. 1H NMR (CDCl3): δ 6.62-6.68 (m, 2H), 6.56-6.60 (m, 1H), 3.80 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][C@H:4]1[OH:16].CN([CH:20]=[O:21])C.C1N=CN(C(N2C=NC=C2)=O)C=1>CCOC(C)=O>[CH2:9]([N:6]1[CH2:7][CH2:8][C@H:3]2[CH2:2][NH:1][C:20](=[O:21])[O:16][C@@H:4]2[CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Reactant: CN(C)C=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=C1NC[C@@H]2CCN(Cc3ccccc3)C[C@H]2O1
Temperature: 65 °C
Yield: 69 %

Procedure:
In a flask, was added (3S,4S)-4-(aminomethyl)-1-benzylpiperidin-3-ol (1.0 g, 4.5 mmol, Sunshine Labs), DMF (10 mL) and CDI (0.736 g, 4.54 mmol). The mixture was heated to about 65° C. for about 40 min. To the mixture was added EtOAc (20 mL) and washed with water (3×20 mL). The aqueous layers were combined and extracted with DCM (2×20 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under vacuum to give (4aS,8aS)-7-benzyloctahydro-2H-pyrido[4,3-e][1,3]oxazin-2-one (0.773 g, 69%): LC/MS (Table 2, Method c) Rt=1.11 min.; MS m/z: 247 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([O:15][CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>C(OCC)(OCC)OCC.FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:24])=[C:4]([C:9]2[C:10]([O:15][CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ncccc1-c1cc(Cl)nnc1N
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: CNc1nnc(Cl)cc1-c1cccnc1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-chloro-4-(2-methoxy-pyridin-3-yl)-pyridazin-3-ylamine (270 mg, 1.14 mmol) in triethyl orthoformate (6 mL) was added 1 drop of trifluoroacetic acid. The reaction mixture was stirred at 100° C. for 3 hours and then concentrated under vacuum (60° C./20 mbar). The residue was dissolved in 5 mL toluene and concentrated again. This was repeated for 3 times to completely remove all volatiles. The residue was dissolved in ethanol (6 mL) and sodium borohydride (86.3 mg, 2.28 mmol) was added in portions at 0° C. The reaction mixture was heated to 90° C. and stirred at this temperature for 2 hours. The reaction was cooled down to 0° C. and the pH was adjusted to 1 by addition of 0.25M aqueous sulfuric acid (5 mL). The yellow reaction mixture was stirred at room temperature for 3 hours, poured on 10% aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL) (pH ca. 8) and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (50 mL). The organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Light yellow solid (100 mg, 35%). MS (ESI+): m/z=251.069 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Br[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([S:9][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[N:8][C:4]=2[CH:3]=1
Reactant: Cn1c(S)nc2cc(Cl)ccc21
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(SC(C(=O)O)c2ccccc2)nc2cc(Cl)ccc21
Yield: 775.4 %

Procedure:
5.96 g (0.03M) of 5-Chloro-2-mercapto-1-methylbenzimidazole of C above, 0.5 g (0.03M) of α-bromophenylacetic acid and 6.0 g (0.06M) of triethylamine are dissolved in methylene chloride (200 ml) and the mixture heated to reflux overnight. The basic solution is washed with a diluted HCl solution and a white solid is collected. The crude material is recrystallized from 5 L of acetonitrile to give 6.0 g (60% yield) of the title compound, m.p. 203°-5° C. dec.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:1][C@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]3[CH2:3]2)=[N:20][CH:21]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](O)C[C@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](Oc3ccc(Cl)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (7R,8aS)-tert-butyl 7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (485 mg, 2 mmol) and 2,5-dichloropyridine (326 mg, 2.2 mmol) in tetrahydrofuran (4 mL) was added potassium tert-butoxide (3 mL, 1 M in tetrahydrofuran). The mixture was stirred at room temperature overnight. The reaction was quenched with water (10 mL), and the crude product was extracted with dichloromethane (2×50 mL). The combined organic fractions were concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 1.80 (m, 2H), 2.06-2.16 (m, 3H), 2.53 (m, 1H), 2.75-2.90 (m, 2H), 3.60 (m, 1H), 3.90-4.10 (m, 2H), 5.25 (m, 1H), 6.83 (d, 1H, J=7 Hz), 7.80 (d, 1H, J=7 Hz), 8.20 (s, 1H); MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:51])[CH2:7][C@@H:8]([NH:33]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:9]([NH:11][C@H:12]([C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:10])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:51])[CH2:7][C@@H:8]([NH2:33])[C:9]([NH:11][C@H:12]([C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)c1ncc(-c2ccc(I)cc2)[nH]1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)CC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of (R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-N-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-succinamic acid tert-butyl ester (1.5 g, 1.88 mmol) (from step 8-G) in methylene chloride (30 mL) was added piperidine (6 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography over silica gel gradient eluted from 100% methylene chloride to 10% v/v methanol/methylene chloride in 30 minutes to give ((R)-3-amino-N-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-succinamic acid tert-butyl ester (0.93 g, 86%). LC-MS: calcd for C26H31IN4O3 [M+H+] 575. Found 575.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: COCCN
Product: COCCNC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-methoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=504.97 (M+H+); retention time=0.74 minutes.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:46]([C:44]3[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:32]4[C:33]([F:39])=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=4[F:30])[N:45]=3)=[O:47])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.3 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (14.1 mg, 0.035 mmol), 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.032 mmol), HATU (30.2 mg, 0.08 mmol) in DMF (0.07 mL) and DIPEA (0.017 mL, 0.095 mmol) was stirred at room temperature for 16 h. The mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (8.0 mg, 38%). LCMS calc. for C34H39F3N5O6 (M+H)+: m/z=670.3. Found: 670.3.
Reaction SMILES: [In].[CH2:2](Br)[CH:3]=[CH2:4].[CH3:6][O:7][N:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH:11]=[C:10]1[OH:20]>CN(C)C=O>[CH2:4]([C:9]1([NH:8][O:7][CH3:6])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH:11]=[C:10]1[OH:20])[CH:3]=[CH2:2]
Reactant: CON=C1C(O)=CC(=O)c2ccccc21
Reactant: C=CCBr
Agent: [In]
Solvent: CN(C)C=O
Product: C=CCC1(NOC)C(O)=CC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of indium powder (0.68 g, 5.9 mmol) in anhydrous N,N-dimethylformamide (2 mL) at 0° C. was added allylbromide (0.76 mL, 8.8 mmol) dropwise over 5 min. The cooling bath was removed and the resulting exothermic reaction was allowed to stir for several minutes, during which time the indium metal dissolved. The resulting solution was cooled to 0° C., and a solution of Example 7A (1.00 g, 4.9 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added. The resulting solution was allowed to warm to rt and stirred 1 h. The reaction mixture was partitioned between H2O (50 mL) and ethyl acetate (3×50 mL), and the combined organic layers were dried over Na2SO4. The solution was filtered and concentrated, and the product was precipitated from diethyl ether to provide the title compound as a light tan powder (0.99 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.84 (s, 1H), 7.85 (d, J=7.7 Hz, 2H), 7.60 (t, J=7.4 Hz, 1H), 7.32-7.48 (m, 1H), 7.14 (br s, 1H), 5.68 (br s, 1H), 5.09 (m, 1H), 4.64-4.81 (m, 2H), 3.11 (s, 3H), 2.20-2.45 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M255) (0.31 g, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained a light yellow solid (220 mg, 89%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[CH3:11][C:12]1([CH3:29])[O:17][C:16](=[O:18])[C:15](=[C:19](SC)[NH:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:14](=[O:28])[O:13]1>ClCCl.CO>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:19]([NH:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[C:15]1[C:14](=[O:28])[O:13][C:12]([CH3:29])([CH3:11])[O:17][C:16]1=[O:18])[CH3:2]
Reactant: CSC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O
Reactant: CCOC(CCN)OCC
Solvent: CO
Solvent: ClCCl
Product: CCOC(CCNC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3,3-Diethoxypropylamine (210.7 g, 1.43 mol) was added in portions to the solution of 2,2-dimethyl-5-(methylsulfanyl-thiophene-3-ylamino-methylene)-[1,3]dioxane-4,6-dione (407.3 g, 1.36 mol) in dichloromethane (1.7 L) and methanol (0.36 L) over 60 min, while the reaction temperature was kept under 25° C. with a water bath. After stirring for 1.5 h at room temperature, the reaction mixture was diluted with dichloromethane (0.8 L). The organic layer was separated and washed with aqueous ammonium chloride solution (400 mL, made of 200 mL of sat. NH4Cl and 200 mL of water), brine (300 mL) and dried over magnesium sulfate. Concentration of the reaction mixture under reduced pressure afforded a dark oil. Xylenes (500 ml) were added and the mixture concentrated under reduced pressure to give the intermediate 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. The resultant dark oil was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.65 (m, 6H), 1.73 (s, 6H), 1.78 (m, 2H), 2.98 (q, 2H, J=6.4 Hz), 3.45 (m, 2H), 3.60 (m, 2H), 4.50 (t, 1H, J=5.2 Hz), 6.98 (dd, 1H, J=1.6, 5.2 Hz), 7.05 (dd, 1H, J=1.2, 3.2 Hz), 7.33 (dd, 1H, J=3.2, 5.2 Hz), 10.2 (s, 1H), 11.3 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Cl.[CH3:19]OCOC.[OH-].[Na+]>CN(C)C=O.O.C1(C)C=CC=CC=1>[ClH:2].[Cl:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:19]1
Reactant: COCOC
Reactant: Clc1ccccc1CNCCc1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 0 °C
Reaction time: 11 h

Procedure:
N-(2-chlorobenzyl)-2-(2-thienyl)-ethylamine hydrochloride (29.2 g, 102 mmole), hydrogen chloride gas (4.5 g, 129 mmoles) and dimethoxymethane (33 ml, 388 mmoles) were combined in dimethylformamide (57 ml). The solution was refluxed and stirred for 11 hours. The dimethylformamide was removed under vacuum while keeping the temperature of the solution at 85° C. A solution of sodium hydroxide (11 g, 275 mmoles) in H2O (87 ml) and toluene (87 ml) was added to the residue and stirred at a temperature less than 55° C. for 30 minutes. The aqueous and organic layers were separated and the aqueous layer washed with toluene (85 ml). The toluene was combined with the organic layer and concentrated under vacuum to 50 ml. The solution was filtered to remove salts. Methanol (17 ml) and HCl gas were added to the solution at a temperature less than 40° C. until a pH of 1.5 was reached. The slurry was heated to a temperature less than 50° C. for one hour and cooled to 0° C. for one hour. The product was isolated, washed with 1:9 methanol/toluene and dried; yielding 87.6% real to real (corrected for assay of starting material) of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (ticlopidine hydrochloride). Characterizing HPLC data indicated 99.3% pure.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23](O)=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O
Product: CS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(methylsulfonyl)acetamide was prepared from [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 59) following General Procedure L, using methanesulfonic acid amide in place of the sulfamide.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:24][CH2:25][CH3:26])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]1([O:11][CH2:12][CH2:13][NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: BrCCOc1cccc2ccccc12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccccc1NCCOc1cccc2ccccc12

Procedure:
A solution of 12.54 g. of 2-(1-naphthyloxy)ethyl bromide and 16.5 g. of ethyl anthranilate in 50 ml. of hexamethylphosphoramide are heated at 110° for 18 hours. After cooling and diluting with water, the mixture is extracted twice with 200 ml. of ether. The combined ether extracts are washed with water, dried and evaporated to a brown oil. The oil is dissolved in 60 ml. of ethanol and chilled in an ice-bath yielding a beige solid which is recrystallized from 100 ml. of ethanol affording pale yellow crystals, m.p. 81°-83° C.