Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([C:12]1[NH:13][C:14](=[N:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=1)[C:9]([OH:11])=O.CN(CC1C=CC=CC=1)C.ClC(OCCCC)=O.[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH2:59])[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1>O1CCCC1.C(N(CC)CC)C>[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH:59][C:9](=[O:11])[CH:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[C:12]4[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=4)[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CS(=O)(=O)N=c1[nH]c(C(OC2CCCCO2)C(=O)O)cs1
Agent: CCCCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-tetrahydropranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (350 mg.), triethylamine (96 mg.), N,N-dimethylbenzylamine (half drop) and tetrahydrofuran (7 ml.) was dropwise added a mixture of butyl chloroformate (130 mg.) and tetrahydrofuran (1 ml.) over 1 minute at -15° C., and then the mixture was stirred for 30 minutes at -15° to -10° C. To the mixture was added all at once a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (224 mg.), triethylamine (80 mg.) and 50% tetrahydrofuran aqueous solution (10 ml.) which was cooled at 0° C., and the mixture was stirred for 30 minutes under ice-cooling and further stirred for 2 hours at room temperature. After the reaction, the reaction mixture was concentrated. The residue was adjusted to pH 8 with 5% sodium bicarbonate aqueous solution and washed with ethyl acetate. Thus obtained aqueous layer was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (270 mg.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2oc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccc(OCc4ccccc4)cc3)ccc2oc1=O

Procedure:
6-(4-Benzyloxy-phenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (example 2-b) and 4-benzyloxyphenylboronic acid under conditions analogous to example 3-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.14 (d, J=2.3 Hz, 1H), 7.85 (dd, J=8.5, 2.3 Hz, 1H), 7.54-7.08 (m, 10H), 5.12 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[NH2:8][CH2:9][CH:10]([NH2:12])[CH3:11].[OH-:13].[Na+]>C(O)C>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH:3]([NH:8][CH2:9][CH:10]([NH:12][CH:3]2[CH2:4][CH2:5][S:1](=[O:6])(=[O:13])[CH2:2]2)[CH3:11])[CH2:2]1
Reactant: O=S1(=O)CC=CC1
Reactant: [OH-]
Reactant: CC(N)CN
Agent: [Na+]
Solvent: CCO
Product: CC(CNC1CCS(=O)(=O)C1)NC1CCS(=O)(=O)C1
Temperature: 85 °C

Procedure:
To a 500 ml round-bottom flask equipped with condenser, thermometer and a stirrer were introduced 118 g. (1.0 mole) of 2,5-dihydrothiophene 1,1-dioxide, 200 ml. of 70% by weight aqueous ethanol and 37 g (0.5 mole) of 1,2-diaminopropane and 10 ml. of a 0.1 N sodium hydroxide solution. The reaction mixture was heated at 85°C for 20 hours. The solvent was then removed under a reduced pressure. The product, N,N'-bis(1,1-dioxotetrahydro-3-thienyl)-1,2-diaminopropane was obtained as a viscous liquid. The infrared spectrum of this product was superimposable with that of Example 3. This product also evaluated in high resiliency, flexible polyurethane foam (see Example 19).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:4]2[N:5]=[C:6]([N:9]3[C:17]4[CH:16]=[C:15]([C:18]5[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=5)[N:14]=[CH:13][C:12]=4[CH:11]=[N:10]3)[CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:26]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C#N)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C#N)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-cyano-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.4859 mmol; 248.6 mg) in dichloromethane (8 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 201 was obtained as an off-white solid (361.6 mg, 18%). 1H NMR (400 MHz, DMSO) δ 9.61-9.55 (s, 1H), 9.48-9.44 (s, 1H), 9.37-9.33 (s, 1H), 8.80-8.75 (s, 1H), 8.66-8.62 (s, 1H), 8.26-8.19 (m, 2H), 7.48-7.44 (d, J=8.4 Hz, 1H), 4.29-4.19 (dd, J=10.7, 6.9 Hz, 2H), 3.00-2.94 (m, 1H), 2.66-2.62 (s, 3H), 2.03-1.89 (dd, J=18.5, 10.2 Hz, 2H), 1.80-1.66 (m, 1H), 1.49-1.37 (m, 1H); MS (ESI) m/z: 412.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[CH:6]=1.CS[C:14](SC)=[C:15]([C:19]#[N:20])[C:16]([NH2:18])=[O:17].[NH2:23][CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]1=[O:38]>C(O)C>[C:19]([C:15](=[C:14]([NH:23][C@H:24]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]1=[O:38])[NH:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[CH:6][C:5]=2[CH:7]=1)[C:16]([NH2:18])=[O:17])#[N:20]
Reactant: NC1CCCCN(Cc2ccccc2)C1=O
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Cc1cc2cc(N)ccc2o1
Solvent: CCO
Product: Cc1cc2cc(NC(N[C@H]3CCCCN(Cc4ccccc4)C3=O)=C(C#N)C(N)=O)ccc2o1
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Preparation of title compound. A solution of 2-methyl-5-benzofuranamine (32 mg, 0.22 mmol) and 3,3-bis(methylthio)-2-cyanoacrylamide (41 mg, 0.22 mmol) in ethanol (0.35 mL) was stirred at 80° C. After stirring for 5 h, a solution of 3-aminohexahydro-1-phenylmethyl-2H-azepin-2-one (74 mg, 0.29 mmol) in ethanol (0.74 mL) was added. After stirring at 80° C. for 2 days, the reaction was purified by column chromatography (silica, 1% methanol/dichloromethane) to afford the title compound (37 mg, 37% yield): MS (ESI, pos. ion spectrum) m/z 458; HPLC (method A) tR 4.13 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1.[CH:20]([O-])([O-])OCC>C(O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH:20]=[C:15]2[C:16](=[O:17])[O:18][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC([O-])[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2ccc(C#N)cc2)C(=O)O1
Temperature: 120 °C
Yield: 71.2 %

Procedure:
A mixture of p-aminobenzonitrile (2.00 g), Meldrum's acid (2.56 g), ethyl orthoformate (2.76 g) and ethanol (10 ml) was heated at 120° C. (bath temperature) to evaporate the ethanol. Ethyl acetate was added to the obtained orange solid. The solid was pulverized, collected by filtration and washed with ethyl acetate to give the object compound (3.28 g) as a white powder.
Reaction SMILES: [CH3:1][CH2:2][CH:3](O)[CH2:4][CH2:5][CH2:6][CH3:7].[NH3:9]>>[CH3:1][CH2:2][CH:3]([NH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:1])[CH2:4][CH2:5][CH2:6][CH3:7].[CH3:1][CH2:2][CH:3]([NH2:9])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(O)CC
Reactant: N
Product: CCCCC(CC)NC(CC)CCCC
Product: CCCCC(N)CC

Procedure:
If heptan-3-ol is reacted similarly with ammonia at 130° C., 80% of theory of di-3-heptylamine, 18.5% of theory of 3-heptylamine and 0.5% of theory of unconverted alcohol are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:24])(=[O:3])[CH3:2].[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][Br:29]>>[Br-:29].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH3:28])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:24])(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1C(C)=O)C2
Reactant: Cc1ccccc1CBr
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3ccccc3C)cc1C(C)=O)C2
Product: [Br-]

Procedure:
The title compound 142 is prepared according to the procedure reported in Example 38.1 with compound 32 (130.1 mg, 0.4 mmol) and 2-methylbenzyl bromide (90 μL, 0.68 mmol) as reactants. White solid. (Yield 130 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[N:7]=C(NC)[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH2:32]([NH2:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[CH3:40][N:41]([CH3:44])[CH:42]=[O:43]>>[Br:1][C:2]1[N:7]=[C:40]([N:41]([CH3:44])[C:42]([NH:39][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:43])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCCCCCCN
Reactant: CNc1cccc(Br)n1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCNC(=O)N(C)c1cccc(Br)n1
Temperature: 130 °C
Yield: 80 %

Procedure:
1 g (5.35 mmol) of (6-bromopyrid-2-yl)-N-methylamine, 1 ml of diisopropylethylamine and 1.6 g (8 mmol) of 4-nitrophenyl chloroformate are heated at 130° C. for 15 minutes by microwave. 1.2 ml (8 mmol) of heptylamine and 7 ml of dimethylformamide are added and the reaction medium is heated at 130° C. for a further 5 minutes. The residue obtained is purified by thin-layer chromatography on silica eluted with a 70/30 heptane/ethyl acetate mixture. 1.4 g (80%) of 1-(6-bromopyrid-2-yl)-3-heptyl-1-methylurea are obtained in the form of a yellow solid.
Reaction SMILES: Cl.[CH2:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][CH2:4][NH:3]1.[O:15]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1C=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:30]([O-])(=O)C.[K+].S1C=CC=C1>CO.[Pd]>[O:15]([C:16]1[CH:17]=[CH:18][C:19]([CH2:30][N:3]2[CH2:4][CH2:5][C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[CH2:2]2)=[CH:20][CH:21]=1)[C:22]1[CH:23]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccccc1Oc1ccccc1
Reactant: CC(=O)[O-]
Reactant: c1ccc2c3c(sc2c1)CNCC3
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: c1ccsc1
Solvent: CO
Product: c1ccc(Oc2ccc(CN3CCc4c(sc5ccccc45)C3)cc2)cc1
Yield: 72.7 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine hydrochloride (1:1) (0.01 mol) and phenoxybenzaldehyde (0.01 mol) in methanol (150 ml) was hydrogenated at 50° C. with Pd/C 10% (1 g) as a catalyst in the presence of potassium acetate (2 g) and thiophene 4% (1 ml). After uptake of H2 (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from CH3CN, filtered off and dried. This fraction (3 g) was stirred in water with a little NH4OH, and this mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated. The residue was crystallized from CH3CN, filtered off and dried, yielding 2.7 g of 1,2,3,4-tetrahydro-2-[(4-phenoxy-phenyl)methyl]benzothieno[2,3-c]pyridine (compound 34).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.ClCCl.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Yield: 78.3 %

Procedure:
To 14.32 g (60 mmol) of said 4,4'-difluorobenzhydryl chloride were added 10.46 g (90 mmol) of anhydrous sodium carbonate, 25.84 g (300 mmol) of piperazine and 52 ml of dry chloroform, and the mixture was heated under reflux. To the reaction mixture was added dropwise over 45 minutes 14.32 g (60 mmol) of 4,4'-difluorobenzhydryl chloride in 13 ml of dry chloroform. The mixture was heated under reflux for 18 hours and filtered. The filtrate was washed successively with water and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. There was obtained a residue, which was subjected to column chromatography on silica gel to give 13.49 g (47 mmol) of 4,4'-difluorobenzhydryl piperazine from eluates of dichloromethane-methanol (10:1).
Reaction SMILES: C(S[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C)[CH:13]=2)[NH:8][C:7]=1[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].CCS.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl>[OH:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:6]2
Reactant: COC(=O)C(C)(C)Cc1[nH]c2ccc(OC)cc2c1SC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of the compound from step A (25.50 g, 73 mmol) in CH2Cl2 (250 ml) at 0° C. was added AlCl3 (87.70 g, 9 mol eq.) portion-wise. When the addition was complete, the ice-bath was removed and the mixture was stirred at RT for 3 hours. EtSH (27 ml, 5 mol eq.) was added and the resulting mixture was stirred for a further 5 hours. It was then slowly poured onto an ice-cold 1M solution of Na, K tartrate. The product was extracted into CH2Cl2 (×2) and the organic phase was washed with aq. NaCl (×3). Conventional work-up followed chromatography on silica gel using EtOAc/hexane 1:5 to 3:2 afforded 13.60 g of the title compound, 75% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C.O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCSc1nnc(N)s1
Reaction time: 2 h
Yield: 77.1 %

Procedure:
In 190 ml of ethanol and 240 ml of water, 81.5 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 26.9 g of sodium hydroxide were added. To this solution, 99 g of 1-bromohexane was added and the resulting mixture was warmed to 60°~70° C. and stirred for 2 hours. After cooling, water was added to the reaction mixture, and the resulting solution was filtered. The residue was washed with water and dried under reduced pressure. The dried residue was recrystallized from an ethanol/hexane mixture, and thus 100.5 g of 2-amino-5-hexylthio-1,3,4-thiadiazole was obtained. m.p. 113°~115° C. Yield 77%.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1ccnc(Br)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3cc(C)ccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromo-4-methylpyridine
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)N1CC=C(c2coc3c(O[C@H](C)c4c(Cl)ccc(F)c4Cl)c(N)ncc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask were added 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), isopropyl isocyanate (0.00371 g, 0.0436 mmol), DIPEA (33 μL, 0.19 mmol) and DMF (1 mL) and the reaction mixture was stirred at rt for 15 min. Purification by HPLC followed by prep TLC in 5% NH3 in DCM afforded the title compound. 1H NMR (400 MHz, CD3OD): δ=1.17 (d, J=6.6 Hz, 6H), 1.88 (d, J=6.8 Hz, 3H), 2.49 (br. s., 2H), 3.63 (t, J=5.7 Hz, 2H), 3.87-3.99 (m, 1H), 4.06 (d, J=2.5 Hz, 2H), 6.13 (d, J=7.6 Hz, 1H), 6.25 (br. s., 1H), 6.49 (d, J=6.8 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H). MS (ES+): m/z 507.04/509.06 (100/71) [MH+]. HPLC: tR=3.14 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:25](O)(=[O:28])[CH2:26][CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:25](=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)O
Reactant: Cc1cc(O)cc(=O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1c(O)cc(C)oc1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 4-hydroxy-6-methyl-2H-pyran-2-one (18 g; 143 mmol; Aldrich) in 300 ml DCM at 0° C., was added TEA (20 ml; 143 mmol; Aldrich), DCC (30 g; 145 mmol; Aldrich), DMAP (5.25 g; 42.7 mmol; Aldrich) and propionic acid (11 ml; 147 mmol; Aldrich). The reaction mixture was stirred at 0° C. for 1 h, stirred at 25° C. for 18 h, and filtered via vacuum filtration. The filtrate was washed with 5% HCl, dried with brine and anhydrous Na2SO4, and evaporated to a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH:18](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH:18](=[C:22]1[CH2:27][CH2:26][N:25]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]2[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Reactant: CCCC=C1CCNCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Yield: 54 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04)_(0.718 g, 2.06 mmol) and 4-Butylidenepiperidine (0.301 g, 2.16 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF06) (0.40 g, 54%). 1HNMR (CDCl3) d 7.01 (dd, J=3.0 Hz, J=10.2 Hz, 1H), 6.90 (dd, J=5.4 Hz, J=8.6 Hz, 1H), 6.89-6.63 (m, 1H), 5.12 (t, J=7.4 Hz, 1H), 4.63-4.51 (m, 2H), 4.02-3.89 (m, 1H), 2.51-2.44 (m, 2H), 2.32-2.23 (m, 5H), 2.21-2.15 (m, 5H), 2.11-2.03 (m, 1H), 1.98-1.93 (m, 2H), 1.39-1.29 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) d 164.8, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.7 Hz), 136.2, 130.0 (d, J=10.8 Hz), 122.7, 117.6 (d, J=9.3 Hz), 109.5 (d, J=23.1 Hz), 103.4 (d, J=29.1 Hz), 67.8, 63.7, 56.6, 55.8, 45.7, 36.2, 29.4, 29.3, 28.4, 23.3, 17.0, 13.9.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>O>[C:26]([O:25][C:23]([CH2:22][O:21][N:20]=[C:14]([C:12]1[N:13]=[C:9]([NH:8][CH:6]=[O:7])[S:10][CH:11]=1)[C:15]([OH:17])=[O:16])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
Sodium bicarbonate (4.2 g.) was added to a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (10 g.) in water (500 ml.) to prepare a solution. t-Butyl 2-aminooxyacetate hydrochloride (8.1 g.) was added to the solution and stirred at ambient temperature for 3 hours while adjusting to pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (11.3 g.), mp. 117° C. (dec.).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[CH2:1]([N:4]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Dipropylamine (22.3 g, 0.22 mol) was added to a stirred solution of diethyl bromomalonate (47.8 g, 0.20 tool) in THF (400 mL) and the solution was stirred for 18 hours at room temperature. The precipitate of dipropylamine hydrobromide was filtered off and washed with THF. The THF phase was evaporated and the residual oil was partitioned between ethyl acetate (200 mL) and sodium hydroxide solution (10 mL of 4 N). The ethyl acetate phase was separated, washed with water (2-10 mL), and the solvent was removed under reduced pressure. The residual oil was dissolved in an equal volume of hexane and was applied to a silica gel column (420 g) which was eluted initially with ethyl acetate:hexane (1:20). The concentration of ethyl acetate in the eluant was increased slowly until all the diethyl (dipropylamino)malonate was eluted from the column. Fractions containing the compound as determined by TLC and GC were pooled and the solvent was removed to give diethyl (dipropylamino)malonate as an oil in 80-90% yield.