Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH2:6][C@@H:5]([C:7]([NH2:9])=[O:8])[NH:4][CH2:3]1.CCN(CC)CC.[Cl:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH2:18][C:19]([N:4]1[C@H:5]([C:7]([NH2:9])=[O:8])[CH2:6][S:2][CH2:3]1)=[O:20]
Reactant: NC(=O)[C@@H]1CSCN1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CSCN1C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a stirred suspension of the hydrochloride salt obtained in step III (16.5 g, 0.1 mol) in dichloromethane (200 mL) cooled to 0° C. were added Et3N (41 mL, 0.3 mol) and chloroacetyl chloride (8.8 mL, 0.11 mol). The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mass was filtered through a sintered funnel, the salt bed was washed with ether, and the filtrate was evaporated under vacuum to obtain the crude product (4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carboxamide (20.8 g) as viscous liquid, which was used in the next step without further purification. m/z (M+1) 209; IR cm−1 3418, 2925, 1736, 1667, 1416, 1219, 771; 1H NMR (CDCl3) 300 MHz δ 6.60-6.30 (s (br), ½H), 6.0-5.65 (s (br), ½H), 5.02 (dd, J=3.6, 6.9 Hz, 0.8H), 4.88-4.75 (m, 0.4H), 4.70 (d, J=8.8 Hz, 0.8H), 4.62 (d, J=8.8 Hz, 0.8H), 4.51 (d, J=10.0 Hz, 0.2H), 4.16 (s, 1.6H), 4.11 (s, 0.4H), 3.56 (dd, J=3.4, 11.8 Hz, 0.8H), 3.44 (dd, J=4.7, 8.0 Hz, 0.4H), 3.15 (dd, J=7.1, 11.8 Hz, 0.8H), 1.28 (s, 1.6H), 1.25 (s, 7.4H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl.C(Cl)(Cl)Cl.CCCCCC>[CH2:1]([S:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CCS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.9 %

Procedure:
To a homogeneous solution of 600 mg (1.66 mmole) of 17-(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4,16-trien-3-one in a mixture of dry dichloromethane (60 ml) and trifluoroacetic acid (207 mg) was added triethylsilane (230 mg) and the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Since the tlc of an aliquot showed incomplete reaction, more trifluoroacetic acid (207 mg) and triethylsilane (230 mg) were added. After 1.5 hours the starting material had disappeared by tlc. The resulting solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and water, dried (anhydrous sodium sulfate) and evaporated in vacuo to give a solid. This was redissolved in 1:4 hexane chloroform and chromatographed on a 30 g silica gel column. Elution with 1:4 hexane-chloroform, chloroform and 5:95 ethyl acetate-chloroform gave 520 mg of a tlc-homogeneous title compound. Crystallization from acetone-hexane gave 410 mg of an analytical specimen, melting point 223°-225° C., with consistent spectral data.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=4)[C:11]=3[CH:25]=2)=[N:4][N:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=4)[C:11]=3[CH:25]=2)=[N:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)cc4)c3c2)o1
Temperature: 60 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A mixture of methyl 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoate (204 mg, 0.610 mmol), 1 M aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 60° C. for 24 hr. After cooling, the reaction mixture was poured into water, and acidified with 1M hydrochloric acid. The precipitate was collected by filtration, dried, and recrystallized from ethanol to give the title compound (163 mg, yield 83%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH2:30][C:31]2[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=2)[N:23]=1>>[CH3:36][N:35]1[C:31]([CH2:30][O:29][CH2:28][C:24]2[N:23]=[C:22]([NH:1][C:2]3[S:3][C:4]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=4[F:20])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])[CH:27]=[CH:26][CH:25]=2)=[CH:32][C:33]([CH3:37])=[N:34]1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1cc(COCc2cccc(Br)n2)n(C)n1
Product: Cc1cc(COCc2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)n(C)n1

Procedure:
The title compound was prepared as described Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.68 mmol) and 2-bromo-6-{[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]methyl}pyridine (205 mg, 0.68 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].Br[CH2:20][C:21]([N:23]([CH2:30][CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].CC1C(=O)NC(C2C=CC=CC=2)=NC=1C.BrCC(N(CCC)CCC)=O>>[CH2:30]([N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](=[O:22])[CH2:20][O:18][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[N:4]=1)[CH3:31]
Reactant: CCN(C(=O)CBr)c1ccccc1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c(=O)c1C
Agent: CCCN(CCC)C(=O)CBr
Agent: Cc1nc(-c2ccccc2)[nH]c(=O)c1C
Product: CCN(C(=O)COc1nc(-c2ccc([N+](=O)[O-])cc2)nc(C)c1C)c1ccccc1

Procedure:
The same procedures as Example 136 are repeated except that 5,6-dimetyl-2-(4-nitrophenyl)-4-(3H)-pyrimidinone and 2-bromo-N-ethyl-N-phenylacetamide are used instead of 5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone and 2-bromo-N,N-dipropylacetamide, respectively. The product thus obtained is recrystallized from acetonitrile to give the desired compound, m.p. 89-190° C.
Reaction SMILES: IC.[CH2:3](N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[CH2:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([NH:38][S:39]([CH:42]2[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:3][N:38]([C:36]([C:33]1[CH:34]=[N:35][C:30]([O:29][CH2:28][C:18]2[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][C:17]=2[CH3:16])=[CH:31][CH:32]=1)=[O:37])[S:39]([CH:42]1[CH2:44][CH2:43]1)(=[O:40])=[O:41]
Reactant: CCN(CC)CC
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NS(=O)(=O)C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)S(=O)(=O)C2CC2)cn1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
To a solution of mixture of iodomethane (120 μL, 1.91 mmol), triethylamine (245 μL, 1.75 mmol) and anhydrous sodium carbonate (36.9 mg, 0.35 mmol) in DMF (0.5 mL) was added cyclopropanesulfonic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide (44 mg, 0.11 mmol). The reaction mixture was then heated in the microwave for 40 min at 100° C. The mixture was then cooled and evaporated and the residue was purified by chromatography (SiO2, heptane:ethyl acetate 2:1 to 1:1) to give the title compound (3.9 mg, 9%) as a yellow solid. MS: m/e=486.3 [M+OAc]−.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH:12]1[CH2:17][C:16](=O)[CH2:15][CH2:14][O:13]1)=O)C.C1C[O:22]CC1>>[OH:9][CH2:10][C:12]1([OH:22])[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CC(=O)CCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1(O)CCCCO1
Temperature: 0 °C
Yield: 61 %

Procedure:
To a cooled (0° C.), stirred suspension of LiAlH4 (3.42 g, 90.0 mmol) in anhydrous THF (50 mL) was added dropwise a solution of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (5.17 g, 30.0 mmol). After stirring for 1 hour, the reaction was quenched by the slow, sequential addition of water (3.4 mL), 15% NaOH (3.4 mL), and water (10.0 mL). The inorganic salt was filtered off and extracted with EtOAc repeatedly since the product was absorbed on the solid. Solvent removal afforded 2.42 g (61%) of yellow oil. The crude mixture was carried to the next step without purification.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:60])[N:37]([CH2:50][CH2:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[F:49][C:43]1[CH:42]=[C:41]([C:39]2[CH:40]=[C:35]([CH2:32][OH:33])[C:36](=[O:60])[N:37]([CH2:50][CH2:51][CH2:52][C:53]3[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=3)[N:38]=2)[CH:46]=[CH:45][C:44]=1[O:47][CH3:48]
Reactant: COc1ccc(-c2cc(C(=O)O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: COc1ccc(-c2cc(CO)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 37 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one was reacted to yield the title compound as a yellow powder (yield: 37.0%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7](=O)[CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CCO>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=2)[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)c1ccc(CCC(=O)CBr)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(CCc2csc(N)n2)cc1

Procedure:
Thiourea (374 mg, 4.9 mmol) and 21-2 (1.4 g, 4.7 mmol) were combined in 24 mL EtOH and heated to reflux for 1 h. Concentration and flash chromatography (silica, 80% EtOAc/hexane then 10% MeOH/EtOAc) provided 21-3 as a white solid.
Reaction SMILES: N1(CCN2CCC([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])CC2)CCCCCC1.Cl.Cl.Cl.N[CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50][CH2:49]2)[CH2:42][CH2:41]1>>[OH:54][CH:51]1[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][N:43]2[CH2:44][CH2:45][CH:40]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:41][CH2:42]2)[CH2:49][CH2:50]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3-fluoro-phenoxy)-1H-indole-2-carboxylic acid 141 (see example 118) and amine 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:33][OH:34].[K+].[Br-]>>[OH:34][NH:33][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NO
Reactant: CCCCCC#CCC(CC#CCCCCC)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CCCCCC#CCC(CC#CCCCCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 62 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 g of the product isolated. Yield 62%; white solid; mp 83-84° C.; 462.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.82-0.90 (m, 6H), 1.15-1.45 (m, 12H), 1.90-2.05 (m, 4H), 2.86 (brd, J=17.0 Hz, 2H), 3.00 (brd, J=17.0 Hz, 2H), 3.87 (s, 3H), 7.15 (d, J=10.0 Hz, 1H), 7.71 (d, J=10.0 Hz, 1H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm−1): 3344 s, 3208 m, 2930 m, 2870 m, 1677 s, 1592 s; Anal. Calc'd for C25H35NO5S: C, 65.05; H, 7.64; N, 3.03. Found: C, 65.26; H, 7.68; N, 2.90.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].CCN(S(F)(F)[F:25])CC>ClCCl>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([F:25])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(F)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of 4-(4-hydroxy-piperidin-1-yl)benzoic acid ethyl ester (1.25 g. 5 mmoles) in dry dichloromethane (30 ml) at room temperature under an inert atmosphere, it was slowly added DAST (0.97 g, 6 mmoles) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 1 hour and then quenched with aqueous NaHCO3. The organic layer was washed with brine, dried and evaporated. The residue was purified by flash chromatography on silica gel using hexane/EtOAc (70/30) as eluent to give the title compound as a white solid (0.7 g, 56%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([NH:6][C:7]([CH3:12])([C:9]#[C:10][CH3:11])[CH3:8])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH:3]([S:2][CH3:1])[C:4]([NH:6][C:7]([CH3:12])([C:9]#[C:10][CH3:11])[CH3:8])=[O:5]
Reactant: CC#CC(C)(C)NC(=O)CSC
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC#CC(C)(C)NC(=O)C(Cl)SC
Temperature: 0 °C
Reaction time: 2 h
Yield: 143.3 %

Procedure:
The product of Step 1 (0.824 g) was dissolved in carbon tetrachloride (15 ml) with warming. The solution was then cooled to 0° C. and N-chlorosuccinimide (NCS, 0.653 g) was then gradually added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered to remove succinimide and the resulting liquid was evaporated to give 2-(chloro)-2-(methylthio)-N-(2-methylpent-3-yn-2-yl) acetamide as a clear oil (1.4 g), which was used without further purification.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[N:14]=[C:15](Cl)[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[NH:14][C:15](=[NH:1])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]
Reactant: N
Reactant: FC(F)(F)c1cc(Cl)c(N=C(Cl)C(F)(F)C(F)(F)F)c(Cl)c1
Solvent: CCO
Product: N=C(Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 40 ml of ethanol and 10 ml of 28% aqueous ammonia was added 3.9 g (10.0 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionimidoyl chloride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and water was poured into the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 3.70 g of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionamidine (hereinafter referred to as present compound 4).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:18]=2)[CH2:13][C@@H:12]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:10])(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:18]=2)[CH2:13][C@@H:12]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:10]
Reactant: COc1ccc(N2CCN(C(=O)CNC(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C(=O)CN)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 49 %

Procedure:
The intermediate {2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester was dissolved in a 4 N solution of hydrogen chloride in dioxane and stirred for 2 h then evaporated to a solid which was filtered and washed with diethyl ether to afford the title compound as a colorless solid (42 mg, 49% based on trihydrochloride salt). LC/MS (Method A) 4.66 min, [M+1]+ 424.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH:9]=O)[CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40]CC)=[O:39])[CH2:34][CH2:33]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][N:32]2[CH2:33][CH2:34][CH:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37]2)[CH:7]=1
Reactant: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1c(CCN2CCC(C(=O)O)CC2)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of [5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]acetaldehyde (D35) (80 mg) and ethyl 4-piperidinecarboxylate (138 mg) in dichloromethane (DCM) (15 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (74.6 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was dissolved in isopropanol (10 mL) and water (10 mL), sodium hydroxide (50 mg) was added. Stirring continued for 2 h at room temperature. 1M HCl solution was added until PH=6˜7. Then iPrOH was removed by evaporation. The aqueous layer was extracted by EA/THF/MeCN for 3 times. The combined organic layers were concentrated, and purified by Mass Directed AutoPrep to give 1-{2-[5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylic acid (E13) (45 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 1.57 (2H, m), 1.79 (2H, d), 2.06 (2H, t), 2.19 (1H, m), 2.58 (2H, t), 2.87 (4H, t), 3.80 (3H, s), 4.94 (1H, m), 7.45 (1H, dd), 7.51 (1H, d), 7.88 (1H, dd), 8.23 (1H, d), 8.29 (1H, dd). δF (DMSO-d6, 376 MHz): −117.4, −61.3. MS (ES): C27H29F4N3O4S requires 567. found 568.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(OCC)(=O)C>C1COCC1.O.[Cl-].[Na+].O>[CH2:16]([O:15][C:13](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1ccc(O)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 117.6 %

Procedure:
A solution of 4-hydroxybenzylamine (1 g, 8.1 mmol) in THF (20 ml) and water (20 ml) was cooled down to 0° C. with sodium hydroxide (357 mg, 8.9 mmol). Benzyl chloroformate (1.27 ml, 8.9 mmol) was added slowly and the reaction mixture was stirred at 0° C. for 1 h and at r.t. for 18 hours. Brine (20 ml) and ethyl acetate (20 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (20 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to yield a light pink solid (2.45 g, 100%). 1H NMR (300 MHz, CDCl3), δ: 4.30 (2 H, d, J=5.8 Hz, CH2NH), 5.15 (2 H, s, OCH2), 6.67 (1 H, br. s, NH), 6.78 (2 H, d, J=8.5 Hz, Ar), 7.12 (2 H, d, J=8.1 Hz, Ar), 7.29-7.44 (5 H, m, Ar)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:20]([C:22]([O:24][CH3:25])=[O:23])#N>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:20][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1]
Reactant: N#Cc1cccc(Cl)c1
Reactant: COC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-{5-[2-tert-Butyldimethylsilanyloxy)ethyl]imidazol-1-ylmethyl}-3-chlorobenzonitrile (1.7 g, 4.52 mmol) is dissolved in anhydrous THF (30 mL) and stirred at −78° C. before a THF solution of LHMDS (8.1 mL, 1.0 M) is added. After 15 min, methyl cyanoformate (0.38 mL, 4.74 mmol) is added and the solution is left at −78° C. for 2 h. The excess LHMDS is quenched with aqueous saturated NH4Cl and the mixture is allowed to warm to room temperature. The mixture is then diluted with EtOAc and washed with aqueous saturated NH4Cl (2×). Organic is dried (Na2SO4) and evaporated. The crude residue is purified via flash column chromatography (EtOAc/hexanes 1:1→EtOAc) to give {5-[2-tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(2-chloro-4-cyanophenyl)acetic acid methyl ester as an oil. MS (ESI) m/z 434.3, 436.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1C[O:16][CH2:15]C1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:15](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: C1CCOC1
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
To a solution of 2-amino-5-methoxy-benzoic acid (1.2 g, 7 mmol) in anhydrous THF (50 mL) triethylamine (1.0 mL, 7 mmol) was added and the mixture was cooled down to 0° C. Then triphosgene (2.0 g, 7 mmol) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. 1 mL of H2O was carefully added to the mixture and the solvent was removed under reduced pressure. The residue was precipitated from H2O, affording 1.3 g of the titled compound (96% yield).