Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:7]3[C:8]([O:12][C:13]4[N:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[C@:21]([CH3:25])([CH2:23][CH3:24])[NH2:22])=[CH:15][CH:14]=4)=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4]1)[CH2:3][CH2:2]2.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:23]([C@@:21]1([CH3:25])[NH:22][C:28](=[O:30])[N:19]([C:16]2[CH:17]=[N:18][C:13]([O:12][C:8]3[C:7]4[C:1]5([CH2:4][O:5][C:6]=4[CH:11]=[CH:10][CH:9]=3)[CH2:2][CH2:3]5)=[CH:14][CH:15]=2)[C:20]1=[O:26])[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Reaction time: 3 h

Procedure:
To a solution of N1-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]-D-isovalinamide (Intermediate 93, 68 mg) and TEA (0.134 mL, 0.962 mmol) in dry dichloromethane (11 ml) at 0° C. was added dropwise a solution of triphosgene (25.7 mg, 0.087 mmol) in dry dichloromethane (3.14 m) and the mixture thus obtained was stirred at the same temperature. After 1 hour a solution of triphosgene (25.7 mg, 0.087 mmol) in dry dichloromethane (3.14 ml) was added. After 3 hours UPLC/MS showed the absence of the starting material and the presence of the desired compound. Water was then added, the organic phase was separated and the aqueous one was extracted again with dichloromethane. The organic phase was washed with brine, dried over sodium sulphate and concentrated under vacuum to give 87 mg of crude. This was purified by flash chromatography (Biotage KP-Sil 10 g SNAP column, eluant cyclohexane/ethyl acetate from 88/12 to 0/100 in 10CV) to give 47 mg of the title compound as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:35][CH2:36][C:37](Br)=[O:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:37](=[O:38])[CH2:36][Br:35])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)CBr)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, bromoacetyl bromide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3([OH:16])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[BH4-].[Na+].O.[CH3:20]O>>[CH3:20][N:12]1[CH2:13][CH2:14][CH2:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)([OH:16])[CH2:11]1
Reactant: CO
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CN1CCCC(O)(c2cccc3[nH]ccc23)C1
Reaction time: 0.25 h

Procedure:
5.8 g of a solution of 40% aqueous formal were added at 0° to -5° C. to a mixture of 13.3 g of 3-(1H-indol-4-yl)-3-piperidinol in 120 ml of methanol and after stirring the mixture for 15 minutes, 4.9 g of 95% sodium borohydride were added thereto. Water was added to the mixture which was then extracted with chloroform containing 20% of methanol. The organic phase was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the 11.8 g of residue were crystallized from benzene to obtain 9 g of 1-methyl-3-(1H-indol-4-yl)-3-piperidinol melting 145° C.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]([NH2:11])[CH3:10].[CH3:12][C:13]1[N:14]=[C:15]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[C:22]2=[O:38])[S:16][C:17]=1[C:18](O)=[O:19]>>[CH2:9]([NH:11][C:18]([C:17]1[S:16][C:15]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=3)[C:22]2=[O:38])=[N:14][C:13]=1[CH3:12])=[O:19])[CH3:10]
Reactant: CCN
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: CCNC(=O)c1sc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)nc1C
Yield: 25 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with ethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 25% yield: mp 218-219° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.60 (s, 1H), 4.47 (s, 2H), 4.10-4.04 (m, 2H), 3.51-3.35 (m, 4H), 2.57 (s, 3H), 1.18 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 157.0, 155.4, 152.3, 148.9, 134.4, 129.7, 121.4, 120.4, 117.8, 47.3, 42.0, 41.8, 35.1, 34.8, 17.0, 14.8: MS (ES+) m/z 429.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.9 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (54.9 mg, 45%).
Reaction SMILES: [ClH:1].C([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][NH:23][C:24]([NH2:26])=[NH:25])[CH2:18][CH2:17]1)=[O:15])=[O:6])C.CO.[OH-].[Na+]>O>[ClH:1].[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C@H:16]1[CH2:17][CH2:18][C@H:19]([CH2:22][NH:23][C:24]([NH2:26])=[NH:25])[CH2:20][CH2:21]1)=[O:15])([OH:6])=[O:4]
Reactant: CCOC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)O)CC1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To N-(o-ethoxycarbonylphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (25.4 g, 0.063 mole) (which is prepared in the same manner as described in Example 1) is added methanol (130 ml), and the mixture is heated to 50° C., and thereto is added a solution of NaOH (7.16 g, 0.179 mole) in water (65 ml), and the mixture is stirred at 50°-60° C. for 45 minutes. The reaction mixture is ice-cooled, and the white precipitates are separated by filtration, suspended in methanol (100 ml) and dissolved by adding thereto 4N-hydrochloric acid (21 ml). After evaporation of the solvent under reduced pressure, the residue is recrystallized from water-methanol (4:1), and the crystals thus obtained are again recrystallized from water-methanol (3:1) to give N-(o-carboxyphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (19.3 g) as white crystals. The physical data of this compound are identical with those of N-(o-carboxyphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride as obtained in Example 3.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])C)[C:27]([O:29]C)=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN(C4(C(OC)=O)CC4)C3=O)=CC=2)=CC=1.FC(F)(F)C1C=CC(C([Cl:66])=O)=CC=1>>[Cl:66][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C:26]5([C:27]([OH:29])=[O:28])[CH2:33][CH2:31]5)[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CC1
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2(C(=O)O)CC2)C3)cc1)c1ccc(Cl)cc1
Yield: 93 %

Procedure:
The compound of example 588 was prepared analogous to compound of example 97 by reaction of compound of example 584 with 4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH:12](O)[CH:11]=[C:10]([CH3:15])[CH2:9]1.[S]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1
Reactant: CC1=CC(O)CC(c2ccccc2F)C1
Agent: [S]
Product: Cc1cccc(-c2ccccc2F)c1
Reaction time: 60 h

Procedure:
A mixture of 5-(2-fluorophenyl)-3-methyl-2-cyclohexen-1-ol (16.6 g, 0.08 mole) and sulfur (7.8 g, 0.24 mole) was heated at 180°-230° for 7.5 hours. The reaction mixture then stood at room temperature for approximately 60 hours before it was distilled under reduced pressure to give 2'-fluoro-3-methyl[1,1'-biphenyl].
Reaction SMILES: [C:1]([C:3](=[N:7][OH:8])[C:4]([NH2:6])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:15][CH2:16]Br>CS(C)=O.CN(C)C=O>[C:1]([C:3](=[N:7][O:8][CH2:16][F:15])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: FCBr
Reactant: N#CC(=NO)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: N#CC(=NOCF)C(N)=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
2-Cyano-2-hydroxyiminoacetamide (22.6 g) was dissolved in dimethyl sulfoxide (100 ml), and then potassium carbonate (55.2 g) was added thereto with stirring at room temperature, and the solution was further stirred for additional 20 minutes. Fluorobromomethane (27 g) dissolved in dimethylformamide (20 ml) was then added to the solution, and the solution was stirred for 20 hours at room temperature and then allowed to cool. The reaction solution was added to ice water (1 liter), and extracted twice with ethyl acetate (150 ml). The organic layer was washed twice with a saturated brine, and dried with addition of anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was washed with ethyl ether, and dried to obtain the objective product (14.4 g).
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].[CH3:8][N:9]([C:13](Cl)=[O:14])[C:10](Cl)=[O:11].[OH-].[Na+]>C1C=CC=CC=1.O>[CH3:8][N:9]1[C:13](=[O:14])[NH:7][CH:4]([S:5][CH3:6])[N:3]([CH3:2])[C:10]1=[O:11]
Reactant: CN(C(=O)Cl)C(=O)Cl
Reactant: CNC(=N)SC
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CSC1NC(=O)N(C)C(=O)N1C
Yield: 75 %

Procedure:
23.2 g (0.1 mole) of N,S-dimethyl-isothiourea hydroiodide were initially introduced into 100 ml of water and 250 ml of benzene. 15.6 (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 12 g (0.3 mole) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from two dropping funnels with vigorous stirring. The reaction took place strongly exothermically. The mixture was stirred for a further hour, any product which precipitated was filtered off, and the benzene phase was separated off, dried over calcium chloride and evaporated in vacuo. The residue, together with the filter residue, was recrystallized from isopropanol. 14 g (75%) of 1,3-dimethyl-4-methylmercapto tetrahydro-1,3,5-triazine-2,6-dione were obtained as a colorless powder of melting point 137°-139° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])/[CH:29]=[N:30]/[S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32]>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C@@H:29]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41]
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(C(F)(F)F)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)c(F)c1)c1ncccn1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(tributylstannyl)pyrimidine (425 mg, 1.151 mmol) in THF (3 mL) at −78° C. was added n-butyllithium (0.720 mL, 1.151 mmol) (1.6 M in hexanes). The reaction was stirred at −78° C. for 1.5 h and then (S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (408 mg, 1.382 mmol) in THF (1 mL) was added. The cooling bath was then removed as the reaction was allowed to warm to rt and stirred for 1 h. LCMS showed 2 products with a ratio of 10:1. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and H2O (5 mL). The reaction mixture was extracted with EtOAc (2×5 mL). The organic layers were combined, dried (MgSO4), and concentrated to give the product. Purification by ISCO (12 g SiO2, 20-80% EtOAc/hexanes) gave the major product, (S)—N—((S)-(3-fluoro-4-(trifluoromethyl)phenyl)-(pyrimidin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][C:9]=1[N:10]=[CH:11][N:12](C)[CH3:13])=[O:4].NC1[CH:40]=[CH:39][C:38]([N:41]2[CH2:45][CH2:44][CH:43]([N:46]([CH3:48])[CH3:47])[CH2:42]2)=[CH:37][CH:36]=1>>[C:18]([SiH2:17][O:16][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:13]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:45][CH2:44][CH:43]([N:46]([CH3:48])[CH3:47])[CH2:42]4)=[CH:37][CH:36]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1sc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc1N=CN(C)C
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(-n3cnc4cc(C(O[SiH2]C(C)(C)C)(c5ccccc5)c5ccccc5)sc4c3=O)cc2)C1

Procedure:
5-(tert-Butyl-diphenyl-silanyloxymethyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester was reacted with [1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amine by method A1. The product with the molecular weight of 608.87 (C35H40N4O2SSi) was obtained in this way; MS (ESI): 609 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[CH:38]=[CH:37][N:36]=3)[CH2:12]1)[C:8](=[O:47])[NH:7]2)=[O:5])C.O.CO.[OH-].[Li+]>C1COCC1.CO.C(Cl)(Cl)Cl>[C:29]([O:28][C:26]([NH:25][CH:15]1[C:14](=[O:33])[N:13]2[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[CH:38]=[CH:37][N:36]=3)[CH2:12]2)[C:8](=[O:47])[NH:7][C:6]2([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C12CC1C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3nccc4cc(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N4C3)nccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
To a solution of 14-tert-butoxycarbonylamino-18-(6-methoxy-isoquinolin-1-yloxy)-2,15-dioxo-10-oxa-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester (the product of step 26G, 667 mg, 1.02 mmol) in 25.7 ml of THF was added 2.9 ml of water, 11.4 ml of methanol, and powdered lithium hydroxide (489 mg, 20.4 mmol). The reaction mixture was stirred at rt for 6 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 20.4 ml of 1 N aq. HCl. To the resulting solution was added pH 4 buffer (biphthalate). The organic phase was washed with water, sat. aq. NaCl, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (silica gel, 0–10% methanol/chloroform) gave 446 mg (˜70%) of 14-tert-butoxycarbonylamino-18-(6-methoxy-isoquinolin-1-yloxy)-2,15-dioxo-10-oxa-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as a slightly pink collapsed foam: 1H NMR (500 MHz, METHANOL-D4) δ 0.99–1.16 (m, 1H), 1.22 (s, 9H), 1.50–2.04 (m, 6H), 2.40–2.73 (m, 3H), 3.41–3.50 (m, 1H), 3.51–3.62 (m, 1H), 3.73–3.86 (m, 1H), 3.90 (s, 3H), 4.03 (d, J=10.52 Hz, 1H), 4.21 (d, J=8.31 Hz, 1H), 4.42–4.72 (m, 3H), 5.65 (s, 2H), 5.82 (s, 1H), 7.06 (d, J=9.05 Hz, 1H), 7.15 (s, 1H), 7.22 (d, J=5.87 Hz, 1H), 7.87 (m, J=9.29 Hz, 2H), 8.14 (d, J=8.56 Hz, 1H). LC-MS (Method B, retention time: 1.46 min), MS m/z 625 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].I[CH2:25][CH2:26][CH3:27]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH2:25][CH2:26][CH3:27])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Br
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN1CCN(c2nc3cc(F)cc(F)c3c(Br)c2C)CC1=O
Reaction time: 8 h

Procedure:
The 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (70 mg, 0.200 mmol) was dissolved in THF (2.0 mL). To the solution was added sodium hydride (24.0 mg, 0.98 mmol) (60% dispersion) followed by addition of 1-iodopropane (230 μL, 2.40 mmol). The reaction was stirred overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 80% EtOAc:hexanes) to give 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-propylpiperazin-2-one. Mass Spectrum (ESI) m/e=400.1 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]3[C:14](=[O:15])[C:13]4=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]4[C:11]3=[O:16])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: NC1CCCc2sccc21
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCCc2sccc21

Procedure:
In 50 ml of toluene, 5 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-ylamine, 4.84 g of phthalic anhydride, and 0.5 ml of triethylamine are heated at reflux to azoetropically remove water. After the distillation of water is completed, the mixture is cooled, the crystals are collected and washed with ether to afford N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)phthalimide, m.p. 166° C. to 167.5° C. Oxidation of this compound by the method of Example 1 affords the title compound, m.p. 163° C. to 166° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f5) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:37]([CH3:38])=[CH:36][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:8]([N:10]2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[CH:4][C:3]=1[CH3:39].[C-]#N.[K+].Cl.C1C[O:47]CC1.CO>>[F:1][C:2]1[C:37]([CH3:38])=[CH:36][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:8]([NH:10][OH:47])=[O:9])=[CH:4][C:3]=1[CH3:39]
Reactant: Cc1cc(C[C@H](CCCCNCc2ccc(F)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Reactant: C1CCOC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(C[C@H](CCCCNCc2ccc(F)cc2)C(=O)NO)cc(C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of (R)-3-((S)-2-[4-fluoro-3,5-dimethylbenzyl)-6-(4-fluorobenzylamino)-hexanoyl]-4-benzyloxazolidin-2-one (0.030 g, 0.0561 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), was added KCN (0.001 g, 0.015 mmol). After stirring at room temperature for overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The product was isolated by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.005 g, 23% yield). LC-MS: tR=4.8 min, m/z 391 (M+H)+, 1H NMR (300 MHz, CD3OD) δ 1.27-1.38 (m, 2H), 1.40-1.57 (m, 2H), 1.58-1.75 (m, 2H), 2.19 (s, 6H), 2.20-2.31 (m, 1H), 2.52-2.66 (m, 1H), 2.70-2.82 (m, 1H), 3.00 (t, J=7.91 Hz, 2H), 4.17 (s, 2H), 6.82 (d, J=6.74 Hz, 2H), 7.20 (t, J=8.64 Hz, 2H), 7.51 (dd, J=8.20, 5.27 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28]O)[CH:22]=[CH:23][C:24]=1[Cl:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OCCCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-(3,4-dichlorophenyl)propanol (129 mg, 0.630 mmol) synthesized in (11A) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (130 mg, yield: 73%).