Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH2:32]=O>C(O)(=O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([CH2:32][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:24][CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: C=O
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3cc(CN4CCCCC4)oc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.260 g (0.785 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.12 ml (1.2 mmol) of piperidine and 96 mg (1.2 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([F:14])([F:13])[F:12])[CH2:9][N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7]1)=O)C.O1CCCC1.[OH-].[Na+]>S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC.C(OCC)(=O)C>[CH2:15]([N:8]1[CH2:9][C@@H:10]([C:11]([F:14])([F:12])[F:13])[C@H:6]([CH2:4][OH:3])[CH2:7]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OC[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
A mixed solution of 2.86 g (9.50 mmol) of trans-1-benzyl-4-trifluoromethylpyrrolidine-3-carboxylic acid ethyl ester and 15 ml of absolute tetrahydrofuran is added dropwise to the above suspension over 40 minutes on cooling with ice. After stirring at 0° C. for 1.5 hours, the excess reagent is decomposed by adding several drops of sodium sulfate (decahydrate) and 2N sodium hydroxide. Insoluble matter is removed by filtration under reduced pressure. The filtrate is concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (elusion solvent; n-hexane/ethyl acetate (5/1→5/2 (by volume, hereinafter the same))) to give 2.25 g of the objective substance as a colorless powder (yield 91.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I>CCOCC.CC#N.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7][I:34]
Reactant: II
Reactant: COC(=O)COCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)COCCI
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To solution of methyl(2-hydroxyethoxy)acetate (540 mg), imidazole (411 mg) and triphenylphosphine (1.37 g) in ether (2 mL) and CH3CN (1 mL) was added iodine (1.43 g) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. After insolubles were filterred off, the filtrates were diluted with AcOEt, washed with aq Na2SO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-5:1) to give methyl(2-iodoethoxy)acetate as colorless oil (898 mg).
Reaction SMILES: O.O.[Cl-].[Ca+2:4].[Cl-].[CH3:6][C:7]([C:10]1[CH:11]=[C:12]([C:21]2[S:25][C:24](=[S:26])[NH:23][N:22]=2)[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:9])[CH3:8].C(O)C>O1CCCC1>[Ca:4].[CH3:9][C:7]([C:10]1[CH:11]=[C:12]([C:21]2[S:25][C:24](=[S:26])[NH:23][N:22]=2)[CH:13]=[C:14]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:15]=1[OH:16])([CH3:6])[CH3:8]
Reactant: [Ca+2]
Agent: CC(C)(C)c1cc(-c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: [Ca]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Calcium chloride dihydrate (1.496, 0.0102 mole) is added in one portion to a solution of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxy-phenyl]-1,3,4-thiadiazole-2(3H)-thione (8.11 g, 0.0204 mole) in tetrahydrofuran (80 ml). The resulting mixture is stirred hours at room temperature before absolute ethanol (80 ml) is added. The mixture is stirred overnight at room temperature. The solution is concentrated in vacuo and the residue dissolved in tetrahydrofuran and the product is precipitated by the addition of water. Filtration and drying at 80° C. in vacuo provides 4.7 g (6.8 g theor., 68%) 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione calcium (2:1) (salt), mp 212°-231° C., analyzed for 0.31 hydrate.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=O)=[C:4]([OH:26])[CH:3]=1)=[O:9].[NH2:27][CH2:28][CH2:29][OH:30].[BH4-].[Na+].Cl>C(O)C.O>[OH:26][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:9])[O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]=1[CH2:24][NH:27][CH2:28][CH2:29][OH:30]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: NCCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(CNCCO)c1O2

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added 2-amino-ethanol (1 mmol). The reaction was stirred for half an hour. The reaction was added with sodium borohydride (4 mmol) under ice bath, and stirred for additional 15 min under ice bath and then allowed to react overnight at room temperature. Water (3 mL) was added, the solution was acidified to a pH of 6 with dilute HCl. All of the solvent was removed by rotary evaporation. The residue was redissolved in ethanol and dried over anhydrous magnesium sulfate, filtered, and evaporated by a rotary evaporator to give a white solid product.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:37]([NH2:43])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[O:42]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:37][NH:43][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NCc1ccco1)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 93.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 54 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C@@H:11]([OH:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C@@H:11]([OH:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)C(=O)N(CC(=O)O)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetic acid (130 mg, 0.415 mmol, described in Intermediate 21), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (140 mg, 0.557 mmol, described in Intermediate 9), HOBT (82 mg, 0.535 mmol), and EDC (95 mg, 0.498 mmol) in DMF (2 mL) was stirred at ambient temperature for 6 h. The reaction mixture was partitioned between H2O (50 mL), saturated aqueous NaHCO3 (30 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 90:10, to give the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2169; calculated m/z=547.2151 for C30H29F2N4O4.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8](CCCl)[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1.[CH2:18]([CH2:25][NH2:26])[C:19]1C=C[CH:22]=[CH:21][CH:20]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(O)C.C(O)(C)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([NH:26][CH2:25][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:27]=3[CH3:28])[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: NCCc1ccccc1
Reactant: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: Cc1ccccc1CNC1CN(C)C(=O)c2cc(Cl)cnc2O1
Yield: 47.9 %

Procedure:
To a solution of 6.0 g (0.022 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one in 50 ml of absolute ethanol was added 5.3 g (0.044 mole) of benzylmethylamine and the mixture heated to reflux for three days. The solvent was removed by rotary evaporation, and the residue was taken up in 100 ml of methylene chloride, which was subsequently washed with 2×50 ml of dilute sodium hydroxide and 50 ml water, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Residual benzylmethylamine was removed at 95° C., 0.5 mm Hg. However, the mass spectrum now showed starting material; therefore, the residue was taken up in 50 ml of absolute ethanol. To the resulting solution was added 2.7 g (0.022 mole) of benzylmethylamine and the mixture heated to reflux for 24 hrs. The reaction mixture was subjected to the same work-up as mentioned before. The syrup was treated with oxalic acid in isopropyl alcohol. The resulting crystals were recrystallized from ethanol/isopropyl alcohol to give 4.7 g (47.9%) of white crystals, m.p. 176°-179° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:60]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 418 (MH+).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[C@@H:23]([CH2:26][C:27]#[N:28])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:29]O>CO.C(Cl)Cl>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[C@@H:23]([CH2:26][C:27]([NH2:28])=[O:29])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#CC[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Reactant: OO
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (120 mg, 0.30 mmol, 1.00 equiv) in methanol (8 mL) was added LiOR.H2O (37.8 mg, 0.90 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) in an ice-water bath. The resulting solution was stirred for 2 h at room temperature and diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (20:1) to give 100 mg (80%) of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. MS (ES): m/z 416 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 4.11-4.20 (m, 1H), 3.82-3.89 (m, 1H), 3.72 (s, 4H), 3.09-3.17 (m, 1H), 2.93-2.99 (m, 1H), 2.70-2.82 (m, 1H), 2.65 (s, 4H), 2.47 (s, 2H), 2.27-2.35 (m, 2H), 2.11-2.19 (m, 2H), 2.05-2.10 (m, 2H), 1.40-1.67 (m, 4H).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([O-:27])(=[O:26])=[O:25])[CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])(=[O:3])=[O:2].[Na:28][Na]>>[CH:9]1[CH:10]=[C:5]([S:1]([O-:4])(=[O:3])=[O:2])[CH:6]=[C:7]([P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([O-:27])(=[O:25])=[O:26])[CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([S:1]([O-:4])(=[O:3])=[O:2])[CH:17]=2)[CH:8]=1.[Na+:28].[Na+:28].[Na+:28]
Reactant: O=S(=O)([O-])c1cccc(P(c2ccccc2)c2cccc(S(=O)(=O)[O-])c2)c1
Reactant: [Na][Na]
Product: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Product: [Na+]

Procedure:
TPPDS: Bis(3-sulfonatophenyl)phenylphosphine, disodium salt
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.C[O:27][C:28]([C@H:30]1[CH2:34][C@H:33]([N:35]2[CH:39]=[C:38](I)[CH:37]=[N:36]2)[CH2:32][N:31]1C(OCC1C=CC=CC=1)=O)=[O:29].[F-].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:38]2[CH:37]=[N:36][N:35]([C@@H:33]3[CH2:32][NH:31][C@@H:30]([C:28]([OH:29])=[O:27])[CH2:34]3)[CH:39]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: COC(=O)[C@H]1C[C@H](n2cc(I)cn2)CN1C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cnn([C@@H]3CN[C@@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Temperature: 60 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (151 mg, 0.428 mmol), (2R,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (177 mg, 0.389 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potass fluoride (67.8 mg, 1.17 mmol), and 4:1 dioxane:water (4 mL) was heated in the microwave reactor at 85° C. for 30 min. The solution was dry-loaded onto silica gel for column chromatography, eluting with 2→5% MeOH/DCM. The fractions containing the product were concentrated in vacuo and dissolved in conc. HCl. The material was heated to 60° C. for 3 h in a sealed tube. The solvent was removed on the corrosive pump to afford the title compound as an orange solid. 1H NMR (400 MHz, CD3OD): δ=2.55-2.67 (m, 1H), 2.74 (br. s., 1H), 3.76-3.87 (m, 2H), 4.45 (t, J=8.6 Hz, 1H), 5.25 (dd, J=6.1, 3.0 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.49-7.55 (m, 1H), 7.88 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3](=[N:8][O:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])#[N:2].C[O-].[Na+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)O[C:21](=[O:22])C=2C=1.C(O)(=O)C>CO>[NH:2]=[C:1]([O:22][CH3:21])[C:3](=[N:8][O:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCON=C(C#N)C(=O)OC
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCON=C(C(=N)OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-cyano-2-ethoxyiminoacetate (syn isomer) (4.7 g) in methanol (50 ml) was added 1 N methanolic solution (5 ml) of sodium methoxide under cooling in an ice-bath and stirring, which was continued for 20 minutes in an ice-bath and 15 minutes at room temperature. The mixture was neutralized to the end point of phenolphthalein with 1 N methanolic solution of acetic acid and evaporated. The residue was dissolved in methylene chloride (80 ml), washed with water, dried over magnesium sulfate and evaporated to give methyl 3-imino-3-methoxy-2-ethoxyiminopropionate (syn isomer) (4.8 g) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=[S:5])[S-:4].C[NH2+]C.[N+:10]([CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:12])=[O:11]>CO>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[S:5][CH:14]([CH2:13][N+:10]([O-:12])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: CO
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1
Yield: 51 %

Procedure:
Dimethylammonium dimethyldithiocarbamate (16.6 grams, 0.10 mole) carbon disulfide (7.6 grams, 0.10 mole), and β-nitrostyrene (14.9 grams, 0.10 mole) were dissolved in methanol (50 ml.). A rapid exothermic reaction ensued and the product precipitated. The reaction temperature was held to 35° C. with ice cooling. After several hours at 25° C., the product was filtered off, washed with methanol, and dried in air. The crude product, melted at ca. 103° C.-110° C. and weighed 22.9 grams (85%). Recrystallizations from hot methanol and from acetone-2-propanol solution (without heating) gave 13.8 grams of α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 104° C.-108° C. (prior sintering). The infrared spectrum was essentially identical to the spectrum of analytically pure material.
Reaction SMILES: C([N:8]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[CH2:9][CH2:10][O:11][C:12]1[C:17]([C:18](=[O:20])[NH2:19])=[CH:16][CH:15]=[CH:14][N:13]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([C:17]1[C:12]([O:11][CH2:10][CH2:9][NH:8][CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:20])[NH2:19]
Reactant: [H][H]
Reactant: Cc1ccccc1OCC(O)CN(CCOc1ncccc1C(N)=O)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNCCOc1ncccc1C(N)=O

Procedure:
A solution of 11.7 g of 1-{N-benzyl-N-[2-(3-carbamoyl-2-pyridyloxy)-ethyl]-amino}-3-(2-methyl-phenyloxy)-2-propanol in 120 ml of ethanol is hydrogenated in the presence of 1.2 g of a 5% strength palladium-on-charcoal catalyst at 20°-30° C. and under atmospheric pressure until the uptake of hydrogen ceases. The reaction product is worked up analogously to the process described in Example 1, giving crude 1-[2-(3-carbamoyl-2-pyridyloxy)-ethylamino]-3-(2-methyl-phenyloxy)-2-propanol. A solution of 1.5 g of fumaric acid in isopropanol is added thereto and the neutral fumaric acid salt of 1-[2-(3-carbamoyl-2-pyridyloxy)-ethyl-amino]-3-(2-methyl-phenyloxy)-2-propanol thus obtainable, is recrystallised from a mixture of isopropanol and water; melting point 156° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][O:20][CH2:21][CH3:22].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:30][CH2:31][CH2:32][C:33](ON2C(=O)CCC2=O)=[O:34])C=CC=CC=1.CO>ClCCl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][O:20][CH2:21][CH3:22])[N:5]([O:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][SH:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1OCCN
Solvent: CO
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1OCCNC(=O)CCS
Temperature: 0 °C
Reaction time: 120 h
Yield: 46.7 %

Procedure:
A solution of 1-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (30 mg, 0.10 mmol) and succinimido 3-(triphenylmethylthio)propanoate (54 mg, 0.12 mmol) in dichloromethane (1 mL) was stirred for 24 hours at room temperature. Methanol (1 mL) was added and stirring was continued for another 5 days. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (2 mL) and triethylsilane (0.16 mL) and cooled to 0° C. Trifluoroacetic acid (0.4 mL) was added. The solution was stirred for 30 min; then it was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) to provide 18.2 mg of N-(2-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]oxy}ethyl)-3-mercaptopropanamide as a solid. HRMS (ESI) calcd for C18H24N5O3S+H 390.1600, found 390.1579.