Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Cl)[N:7]=1)([CH2:3][CH3:4])[CH3:2].[CH2:14]([O:16][C:17](=[O:30])[CH:18]([CH3:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:30])[CH:18]([CH3:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH:1]([CH2:3][CH3:4])[CH3:2])[N:7]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: CCC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Product: CCOC(=O)C(C)Cc1cc(F)c(OCc2cccc(SC(C)CC)n2)c(F)c1
Yield: 90.8 %

Procedure:
2-sec-Butylsulfanyl-6-chloromethyl-pyridine (28 mg, 0.13 mmol) in Step C of Preparation Example 5 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (30 mg, 0.13 mmol) in Step B of Preparation Example 34 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 96%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+].O.[OH-].[Na+]>O.CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([S:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSC2CCN(Cc3ccccc3)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(Cc1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
0.37 g (0.00124 mol) of 1-benzyl-4-benzylsulfanyl-piperidine was suspended in a mixture of 20 ml of water/methanol (1:1) and treated with 2.66 g (0.0124 mol) of sodium periodate. The mixture was stirred at room temperature for 3 hrs., 150 ml of water were added, the pH was adjusted to 8-9 with 1N aqueous NaOH, the mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel with methanol/dichloro-methane (1:19). The fraction having Rf 0.31 was the desired product. 0.17 g (44%) of (RS)-1-benzyl-4-benzylsulfinyl-piperidine was obtained as white crystals; m.p. 123°-125`0.
Reaction SMILES: OC(C1[O:5][C:6](=[O:20])[C:7]2[C:12](C=1C1C=CC=CC=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.Br[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)C(=O)O[C:23]=1[CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34].C1(B(O)O)C=CC=CC=1>>[O:20]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:22]([C:31]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:23]([CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[O:5]1
Reactant: CC(NC(=O)OC(C)(C)C)c1oc(=O)c2ccccc2c1Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: OB(O)c1ccccc1
Product: CC(NC(=O)OC(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 22.6 %

Procedure:
The title compound was made in a way similar to that of intermediate B1 from tert-butyl 1-(4-bromo-1-oxo-1H-isochromen-3-yl)ethylcarbamate (Intermediate A3, 500 mg, 1.358 mmol), phenylboronic acid (215 mg, 1.765 mmol), to give the title compound (112 mg, 22.6%) as a yellowish oil.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: N#CC1CNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 119.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (300 mg, 1.3 mmol) and azetidine-3-carbonitrile hydrochloride (231 mg, 1.95 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.68 ml, 3.9 mmol) and HATU (543 mg, 1.43 mmol). The light yellow solution was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 458 mg of [(R)-1-(3-cyano-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][CH3:34])=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[N:33]([C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:34])=[CH:24][CH:23]=1
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Product: Cc1ccc(CCNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)N(C)C(=O)[C@H](CCc2ccccc2)NC(=O)OC(C)(C)C)cc1

Procedure:
Using Procedure D, Boc-homophenylalanine (143 mg) and Nδ-Boc-Nα-methylornithine 2-(4-methylphenyl)ethylamide (crude product from B) afforded titled product (195 mg) as a glassy solid after silica gel chromatography: 1H NMR (400 MHz, CDCl3) δ1.44 (2 s, 18H), 1.63 (m, 2H), 1.83 (m, 2H, 2.33 s, 3H), 2.63-279 (m, 7H), 3.09 (m, 2H), 3.45 (m, 2H), 4.51 (m, 1H), 4.98 (m, 1H), 7.09 (m, 4H) (m, 3H), and 7.31 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH2:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1ccc(C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared as described in Example 67 using 1-chloro-4-methyl-2-nitrobenzene and tributyl(vinyl)stannane, further purified by flash column chromatography and reverse phase chromatography and isolated as a yellow liquid (1.26 g, 65%): 1H NMR (400 MHz, CDCl3) δ57.73 (d, J=0.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.46-7.35 (m, 1H), 7.13 (dd, J=17.3, 11.0 Hz, 1H), 5.71 (dd, J=17.3, 0.9 Hz, 1H), 5.43 (dd, J=11.0, 0.9 Hz, 1H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.71, 138.91, 133.92, 132.31, 130.52, 128.22, 124.63, 118.10, 20.88; EIMS m/z 163 ([M]+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2].CCN(CC)CC.C1COCC1.[SH2:27]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[S:27])[NH2:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2]
Reactant: S
Reactant: CC(=O)n1ncc2cc(C#N)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)n1ncc2cc(C(N)=S)ccc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 1-acetyl-1H-indazole-5-carbonitrile (1.1 g, 6 mmol), Et3N (2.5 mL, 17.8 mmol) and THF (20 mL) was bubbled in H2S gas over 10 min. Stirred at 0° C. for 24 h. Concentrated in vacuo to give a yellow solid which was triturated with CH2Cl2 and filtered insoluble solid to give 1-acetyl-1H-indazole-5-carbothioic acid amide as a yellow solid. MS m/z: 220.0 (M+H). Calc'd for CloH9N3OS 219.26.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH:9]=[CH2:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].[CH2:16](I)[CH3:17]>CN(C=O)C.C1COCC1.O>[C:1]([O:5][C:6](=[O:11])[N:7]([CH2:8][CH:9]=[CH2:10])[CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCN(CC)C(=O)OC(C)(C)C

Procedure:
A solution of 31.44 g allyl-carbamic acid tert-butyl ester (200 mmol) in 300 ml DMF and 30 ml dry THF is treated with 12 g (300 mmol) NaH (60% suspension in mineral oil). The temperature is kept below 40° C. with an cold water bath. When the development of hydrogen gas ceased the reaction mixture is treated, under ice cooling, with 24 ml (300 mmol) ethyl iodide. After 16 h the mixture is diluted with 1 L water and extracted with TBME. The organic layer is washed extensively with water, concentrated under reduced pressure and distilled at 0.3 mmHg, bp. 38-39°, to yield the allyl-ethyl-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([C:23]2[C:24]3[N:25]([N:29]=[C:30]([NH2:32])[N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:21]=1[F:22].C[Si]([C:37]#[N:38])(C)C>CC(O)=O>[F:15][C:16]1[CH:17]=[C:18]([C:23]2[C:24]3[N:25]([N:29]=[C:30]([NH:32][C:11]4([C:37]#[N:38])[CH2:12][CH2:13][N:8]([C:4]5[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=5)[CH2:9][CH2:10]4)[N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Solvent: CC(=O)O
Product: Cc1cc(N2CCC(C#N)(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)ncn1
Temperature: 25 °C
Reaction time: 88 h
Yield: 8.6 %

Procedure:
To a solution of 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b, 100 mg, 0.523 mmol) and 8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (129 mg, 0.523 mmol) in AcOH was added dropwise trimethylsilyl cyanide (196 μL, 1.57 mmol) and the resulting mixture stirred at room temperature for 88 hours. The mixture was then poured onto NaOH (6 M, 6 mL) and stirred for 10 minutes. The precipitate was then filtered off and dried. Purification by chromatography (silica gel, 20 g, 30 to 100% ethyl acetate in heptane) afforded the title compound (20 mg, 9%) as a yellow solid. MS ISP (m/e): 447.4 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:28])[C:25](O)=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[C:66]([O:70][NH2:71])([CH3:69])([CH3:68])[CH3:67]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:28])[C:25]([NH:71][O:70][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:26])(=[O:17])=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)ON
Reactant: C[C@]1(C(=O)O)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)ONC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R,4R)-4-(4-(Benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylic acid (715 mg, 1.76 mmol) was dissolved in DMF (8 mL), and BOP reagent (1.01 g, 2.29 mmol, 1.3 eq), N,N-diisopropylethylamine (1.2 mL, 7.04 mmol, 4.0 eq) and O-(tert-butyl)hydroxylamine hydrochloride (332 mg, 2.64 mmol, 1.5 eq) were sequentially added. The reaction was stirred at room temperature overnight and then diluted with ethyl acetate (200 mL), and washed with water (3×50 mL). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated affording (3R,4R)-4-(4-(benzyloxy)phenylsulfonamido)-N-tert-butoxy-3-methyl-tetrahydro-2H-pyran-3-carboxamide as white fluffy powder that was used in the next step without purification. MS: (M+Na)+=499.0; (M−H)−=475.2.
Reaction SMILES: Cl.[C:2]1([CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][NH2:26])[CH2:21][CH2:20]3)[CH:14]=2)[O:9]1.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CN(C)C=O.O>[C:28]([O:32][C:33](=[O:34])[NH:35][CH2:36][C:37](=[O:38])[NH:26][CH2:25][C@H:22]1[CH2:23][CH2:24][C@@H:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[O:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:27])[CH2:17][CH2:16]3)[CH2:20][CH2:21]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@@H](CN)CC3)ccc2O1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@@H](CNC(=O)CNC(=O)OC(C)(C)C)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 110 mg of [cis-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexylmethyl]amine hydrochloride (0.28 mmol), 75 mg of N-tert-butoxycarbonylglycine (0.43 mmol), 76 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.40 mmol) and 54 mg of hydroxybenzotriazole (0.40 mmol) at room temperature in 2 ml of dimethylformamide 0.16 ml of N-methylmorpholine (1.42 mmol) were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with diluted aqueous sodium carbonate solution, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography using ethyl acetate/heptane/methanol 5:10:1 as eluent. 95 mg of the title compound were isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)c(Br)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
3-Bromo-4-fluorobenzonitrile (10.0 g, 50 mmol, 1 eq) and imidazole (5.1 g, 75 mmol, 1.5 eq) are dissolved in dimethylformamide (100 ml) and carefully admixed with sodium hydride (60% in mineral oil, 3.0 g, 75 mmol, 1.5 eq) under nitrogen at room temperature. The mixture is stirred at 100° C. for 4 hours. After cooling to room temperature, water (10 ml) is added and the mixture is evaporated to dryness. The residue is washed with water and petroleum ether and purified by column chromatography (silica gel, methyl tert-butyl ether/ethyl acetate gradient).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (20 mg, 0.055 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.10 mmol) followed by formation of the dihydrochloride salt to afford the desired product (16 mg, 52%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.02 (t, J=1.9 Hz, 1H), 7.88 (dd, J=11.5, 2.2 Hz, 1H), 5.75-5.65 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.45 (d, J=12.5 Hz, 2H), 2.11-2.01 (m, 3H), 1.75-1.63 (m, 2H), 1.47-1.36 (m, 2H). ESI MS m/z 471 [M+H]+; HPLC>99% (AUC), tR=9.66 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])[CH3:2].[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)(=[O:19])[CH3:18]>>[CH2:1]([O:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[C:14]([O:15][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])[CH3:2]
Reactant: CC(=O)OCCCCBr
Reactant: CCOc1c(O)c2cccc(O)c2oc1=O
Product: CCOc1c(O)c2cccc(OCCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-ethoxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 4-bromobutyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-ethoxy-4-hydroxy-8-(4-acetoxybutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C([OH:11])C>OCC(CO)O>[C:1]([OH:8])(=[O:7])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:11]
Reactant: CCO
Reactant: O=C(O)CCC(=O)O
Solvent: OCC(O)CO
Product: O=C(O)CC(O)C(=O)O
Reaction time: 90 h

Procedure:
During the anaerobic cultivation the pH decreased to 3.25 after 90 hours of cultivation. After this period 19.5 g/l, succinic acid, 25.1 g/l ethanol and minimal levels of glycerol and malic acid were produced (both 0.5 g/L).
Reaction SMILES: [CH2:1](I)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Br:10][C:11]1[C:12]([C:24]([OH:26])=[O:25])=[C:13]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:14][CH:15]=1>CC#N>[Br:10][C:11]1[C:12]([C:24]([O:26][CH2:1][CH3:2])=[O:25])=[C:13]([C:16](=[O:23])[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[S:14][CH:15]=1
Reactant: O=C(c1ccncc1)c1scc(Br)c1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1c(Br)csc1C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.1 %

Procedure:
A mixture of ethyl iodide (3.78 mL, 48.06 mmol), Cs2CO3 (15.66 g, 48.06 mmol) and 4-bromo-2-isonicotinoylthiophene-3-carboxylic acid (5 g, 16.02 mmol) in CH3CN (150 mL) was stirred at room temperature for about 12 h in a 250 mL round-bottomed flask. After completion of the reaction, the solvent was removed under reduced pressure. The reaction mixture was diluted with water and the aqueous layer was back extracted with ethyl acetate (3×100 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated to afford a yellow solution. The resulting mixture was deposited onto silica gel, loaded onto a silica gel column and eluted with 5:1 PE/EtOAc to give the title compound (1.37 g, 25% yield). LC-MS (Method A): m/z 340 (M+H)+, Rt: 1.07 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:36]2[C:41](=[O:42])[C:40]3[S:43][C:44]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[C:39]=3[CH:38]=[N:37]2)[C:5]([CH2:31][O:32]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:36]2[C:41](=[O:42])[C:40]3[S:43][C:44]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[C:39]=3[CH:38]=[N:37]2)[C:5]([CH2:31][OH:32])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)NCCNc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=CC(=O)NCCNc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a mixture of 105f (125 mg, 0.183 mmol) in THF (6 mL), i-PrOH (2 mL) and H2O (2 mL) was added LiOH.H2O (37 mg, 0.915 mmol). The reaction mixture was stirred at rt for 16 h and concentrated. The residue was partitioned between water and DCM. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was washed with EA and dried to give 105 (73 mg, 60%) as gray solid. 1H NMR (500 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.48 (s, 1H),), 8.20 (s, 1H), 8.12 (s, 1H), 7.42 (s, 1H), 7.38-7.32 (m, 2H), 7.23 (t, J=8.0 Hz, 1H), 6.52 (s, 1H), 6.35 (d, J=8.0 Hz, 1H), 6.21-6.15 (m, 1H), 6.05-6.02 (m, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.73 (s, 1H), 4.33 (s, 2H), 3.59 (s, 3H), 3.28-3.25 (m, 5H), 2.93 (bs, 2H), 2.84 (bs, 2H), 1.88 (bs, 4H). ESI-LCMS: m/z=642 [C34H34FN7O5+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21].C(N(CC)CC)C>[Cu]I.C1COCC1>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:16]1[S:17][C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:19])=[CH:3][C:2]=2[F:1])[CH:15]=1)[CH3:21]
Reactant: C#CCN(CC)CC
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 40 °C
Yield: 84.8 %

Procedure:
A stirred mixture of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (965 mg, 2.50 mmol), N,N-diethylprop-2-yn-1-amine (417 mg, 3.75 mmol), copper(I) iodide (24 mg, 0.125 mmol), triethylamine (8.7 mL, 63 mmol), and THF (20 mL) was sparged with N2 for 5 minutes, then tetrakis(triphenyl -phosphine)palladium(0) (144 mg, 0.125 mmol) was added. The sealed reaction was heated to 40° C. for 18 hours. The mixture was concentrated, and then purified by Biotage Flash 40M silica gel chromatography system, eluting with EtOAc followed by 5% MeOH in EtOAc. The product was obtained as a waxy solid (783 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.59 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.53 (m, 3H), 3.86 (br s, 2H), 3.78 (s, 2H), 2.73 (q, J=7 Hz, 4H), 1.19 (t, J=7 Hz, 6H). LRMS (ESI pos) m/e 370 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)CCCc1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)CCCC1CCCCC1
Yield: 77 %

Procedure:
4-Phenylbutanoic acid prepared as described in Example 56, Part A was dissolved in glacial acetic acid (25 ml). Platinum oxide (0.1 g) was added and the solution was hydrogenated in the Paar shaker at up to 55 p.s.i. until hydrogen uptake ceased (6.5 hours). The catalyst was removed by filtration and the acetic acid was removed in vacuo. The product crystallized and was recrystallized from Et2O (20 ml) to give title compound (1.18 g, 77%), m.p. 85°-88° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].C[O-].[Na+].[Cl-:11].[NH4+:12]>>[ClH:11].[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[NH:12])[NH2:7]
Reactant: N#Cc1ncco1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Product: Cl
Product: N=C(N)c1ncco1

Procedure:
Oxazole-2-carbonitrile (0.94 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61, Step B to give the title compound as an offwhite solid (1.25 g, 70%). The compound was characterized by the following spectroscopic data: