Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1nc(C=O)cs1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 3.1 g (15.6 mmol) of ethyl 2-isopropylthiazole-4-carboxylate in 50 ml of dichloromethane was cooled under N2 atmosphere to -78° C. and treated dropwise with 15.6 ml (23.4 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene over a period of 1.5 h. After being stirred for an additional 0.5 h, the solution was quenched with 5 ml of methanol followed by 15 ml of aqueous Rochelle's salt. The resulting mixture was partitioned between chloroform and aqueous Rochelle's salt, dried over Na2SO4, and concentrated to provide 1.37 g (56%) of the crude desired compound, Rf 0.47 (20% ethyl acetate in hexane). 1H NMR (CDCl3) δ 1.45 (d, J=7 Hz, 6 H), 3.39 (heptet, J=7 Hz, 1 H), 8.07 (s, 1 H), 10.00 (s, 1 H). Mass spectrum: (M+H)+ =156.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].Cl[CH:20]([C:26]([O-])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:18][C:26](=[O:27])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1scc(-c2ccc(Br)cc2)c1C(=O)OCC
Yield: 98.4 %

Procedure:
To a solution of 2-amino-4-(4-bromophenyl)-thiophene-3-carboxylic acid ethyl ester (4.00 g, 11.5 mmol) in CH2Cl2 (40 mL) was added ethyl chloromalonate (2.15 g, 14.2 mmol) slowly. The mixture was then heated to reflux for 30 min. The mixture was concentrated under reduced pressure and separated by flash chromatography on silica gel (5–30% ethyl acetate in hexanes) giving the titled compound (4.98 g, 98.5%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:18])[CH:10]=[C:11]([S:15]([CH3:17])=O)[O:12]2)=[C:7]([O:19][CH3:20])[CH:6]=1)([CH3:3])[CH3:2].[OH:21][C:22]1[CH:27]=[CH:26]C(S)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:21][C:22]1[CH:27]=[CH:26][C:17]([S:15][C:11]2[O:12][C:13]3[C:8]([C:9](=[O:18])[CH:10]=2)=[C:7]([O:19][CH3:20])[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=3)=[CH:24][CH:23]=1
Reactant: Oc1ccc(S)cc1
Reactant: COc1cc(OC(C)C)cc2oc(S(C)=O)cc(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A mixture of 146 mg of 7-isopropoxy-5-methoxy-2-methylsulfinylchromone (0.493 mmol ) , 93 mg of 4-hydroxybenzenethiol(0.740 mmol), 102 mg of potassium carbonate (0.740 mmol) and 6 ml acetone was stirred for 2 hours at room temperature. The reaction solution was neutralized with dilute hydrochloric acid and extracted twice with ethyl acetate, and the organic layer was washed with saturated NaCl water and was then dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was subjected to recrystallization from acetone-methanol, to give 102 mg of 2-(4-hydroxyphenylthio)-7-isopropoxy-5-methoxychromone (57% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>C(O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 121.8 g (0.55 mol) of n-decyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 143-145° C./0.5 Torr), yielding 90 g of 4-n-decyloxyphenyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[S:5][C:6]=1[Br:7].Cl.[CH2:12]([O:14][NH2:15])[CH3:13].Cl>N1C=CC=CC=1.O1CCCC1>[CH2:12]([O:14][NH:15][C:8]([C:4]1[S:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9])[CH3:13]
Reactant: O=C(Cl)c1cc(Br)c(Br)s1
Reactant: CCON
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCONC(=O)c1cc(Br)c(Br)s1
Reaction time: 0.5 h

Procedure:
At room temperature, 6.8 g of 4.5-dibromothiophene-2-carboxylic chloride is stirred, in portions, into 6.8 g of O-ethylhydroxylamine hydrochloride in 10 ml of pyridine and 80 ml of tetrahydrofuran. After 30 minutes, dilute hydrochloric acid was added, and the product was filtered off and washed with water. Yield: 5.8 g; m.p.: 117-119° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:28](=[O:30])[CH3:29])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1.[NH2:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46])[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:28](=[O:30])[CH3:29])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1
Reactant: CCC[C@H](N)CCO
Reactant: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)C(C)=O
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)OCC)C(C)=O)cc1OC
Yield: 23.8 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (25 mg) and (S)-3-aminohexan-1-ol (15 mg). The sub-title compound (5.1 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.93 (1H, d), 6.72-6.67 (2H, m), 4.82 (2H, br s), 4.65 (1H, d), 4.56 (2H, s), 4.18-4.08 (3H, m), 3.99 (2H, s), 3.88 (3H, s), 3.65 (2H, s), 3.48-3.42 (1H, m), 3.32-3.26 (1H, m), 2.33 (3H, s), 2.17 (3H, s), 1.84-1.74 (1H, m), 1.46-1.35 (1H, m), 1.23 (3H, t), 1.16-0.97 (4H, m), 0.73 (3H, t); LC-MS: m/z=502.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:46][C:47]1[C:55]2[C:50](=[N:51][CH:52]=[CH:53][CH:54]=2)[O:49][N:48]=1>CN(C=O)C.C1COCC1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:46][C:47]2[C:55]3[C:50](=[N:51][CH:52]=[CH:53][CH:54]=3)[O:49][N:48]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1noc2ncccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3noc4ncccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 8 mL of DMF at 0° C. is added 0.78 mL (0.78 mmol, 1.2 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and a solution of 154 mg (0.972 mmol, 1.1 equiv.) of 3-bromomethyl isoxazolo[5,4-b]pyridine (Abignente, A.; De Capraris, P.; Stein, M. L. Farmaco Ed. Sci. 1975, 30, 992) in 2 mL of DMF is added. The resulting solution is stirred for 2.5 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel MPLC using an Si60 column and hexane/EtOAc 1/1 as eluent afforded 280 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 400 MHz) δ8.57 (dd, 1H, J=1.5, 4.6), 8.23 (dd, 1H, J=1.5, 7.8), 7.39-7.10 (m, 12H), 6.94 (m, 2H), 4.99 (m, 1H), 4.23 (m, 3H), 3.84 (s, 3H), 3.79 (d 1H, J=8.4), 3.57 (dd, 1H, J=5.3, 16.4), 1.06 (d, 6H, J=6.8); low resolution MS (FAB)m/e 590 (MH+), 589 (M+), 425; Anal. (C34H31N5O5) Calcd. C, 69.26; H, 5.30; N, 11.88 Found C, 69.13; H, 5.32; N, 11.84.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:25])=[O:24]
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
A solution of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (prepared as in Example 9, Step 1, 0.5 g, 2.36 mmol) in CH2Cl2 (5 mL) was cooled to 0° C. Et3N (0.5 mL, 3.54 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (0.2 mL, 2.60 mmol). The reaction mixture was allowed to warm up to ambient temperature and stirred for 1 h and diluted with CH2Cl2. The mixture was washed with water, saturated aqueous NaHCO3, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give 0.71 g of the crude 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate as a light brown solid, which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.90 (septet, 1H, J=6.2 Hz), 4.25-4.15 (m, 2H), 4.06 (d, 2H, J=6.6 Hz), 3.01 (s, 3H), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.80-1.65 (m, 2H), 1.30-1.15 (m, 8H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Clc1ccc2ccccc2n1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: Cn1ccc2cc(-c3ccc4ccccc4n3)ccc21

Procedure:
2-(1-Methyl-1H-indol-5-yl)quinoline T453 was prepared using general procedure A from 2-chloroquinoline (32 mg, 0.2 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (51 mg, 0.2 mmol). The product was obtained as off-white solid (22 mg, 42%). 1H NMR (400 MHz, CDCl3): δ 8.43 (dd, J=2.0, 0.8 Hz, 1H), 8.17 (d, J=8.8 Hz, 2H), 8.12 (dd, J=8.8, 2.0 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.80 (dd, J=8.4, 1.6 Hz, 1H), 7.70 (m, 1H), 7.48 (m, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.09 (d, J=3.2 Hz, 1H), 6.60 (dd, J=3.2, 0.8 Hz, 1H), 3.82 (s, 3H); MS (ESI): 259 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].[Cl-]>O.ClCCl>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[O:20][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1O
Reactant: CCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)cnn1CC
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A 30-ml eggplant type flask was charged with 0.25 g (0.69 mmol) of 4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide, 5 ml of dichloromethane, 5 ml of water and 0.09 g (0.69 mmol, 1 equivalent) of potassium carbonate, and 0.11 g (0.76 mmol, 1.1 equivalents) of n-propanesulfonyl chloride was dropwise added with stirring at room temperature. 5 mg of benzyltriethylaminonium chloride (BTEAC) was added, and the mixture was allowed to react at the above temperature for 2 hours and then liquid-separated. An aqueous layer was extracted with dichloromethane. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off to give 0.35 g of a crude product, which was recrystalized from ethanol to give 0.31 g (yield 95%) of 4,5,8-trimethyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([C:26]([OH:28])=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=1)=O)(C)(C)C>ClCCl>[C:24]([C:20]1[CH:19]=[C:18]([CH2:17][C@@H:16]([C:26]([OH:28])=[O:27])[NH2:15])[CH:23]=[CH:22][N:21]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccnc(C#N)c1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C[C@H](N)C(=O)O)ccn1
Reaction time: 3 h
Yield: 95.1 %

Procedure:
Trifluoroacetic acid (10 ml) was added dropwise to a stirred, ice-cooled solution of N-t-butoxycarbonyl-3-(2-cyano-4-pyridyl)-(S)-alanine (Preparation 12; 1.6 g 5.5 mmol) in dichloromethane (10 ml) and the resulting solution stirred for 3 hours at the same temperature then evaporated under reduced pressure. The residue was dissolved in water (5 ml) and the pH of the solution adjusted to 7 with 1M aqueous sodium hydroxide solution before purification by ion-exchange chromatography on Bio Rad AG50W X-8 (H+ form) resin, using an elution gradient of pyridine:water (0:100 to 10:90), to give the title compound (1.0 g) as a white solid. Rf 0.17 (SS 13), m/e 192.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.Br[C:14]1C=C(C)C=CC=1OC.[Li]CCCC.COB(OC)OC>>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][C:6]=1[B:8]([OH:10])[OH:9]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1ccc(C)cc1Br
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(C)cc1B(O)O
Yield: 96 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-methylanisole (2.00 g, 9.94 mmol), n-BuLi (2.5 M in hexanes; 4.00 mL, 10 mmol), and trimethylborate (3.4 mL, 30 mmol) to afford 1.60 g (96%) of 2-methoxy-5-methylphenylboronic acid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.C([O-])(=O)C.[K+].[N:30]#[C:31]Br.C(Cl)Cl>CO>[Br:17][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][C:10]1[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][C:15]=1[C:2]12[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:31]([NH2:30])=[N:1]1
Reactant: N#CBr
Reactant: NC1(c2ccccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NC1=NC2(c3ccccc3O1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)phenol (0.406 g, 1.006 mmol) in MeOH 5 mL was added potassium acetate (0.126 mL, 2.012 mmol) followed by the dropwise addition of cyanogen bromide, 3.0M solution in DCM (0.402 mL, 1.207 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated, washed with sat. NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated. The resulting product was dissolved in 1,2-dichloroethane followed by the addition of 4.0 M HCl in dioxane (15 mL) and stirred at RT for 1.5 h. The reaction mixture was concentrated, diluted with dichloromethane and washed with saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, concentrated. The crude material was purified by chromatography on silica gel using gradient of 0-100% EtOAc/hexanes to give the desired product. MS m/z=429.8 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([CH2:2][C:3]([NH:5][C:6]2[CH:26]=[CH:25][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Reactant: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Yield: 92 %

Procedure:
Prepared from 2-chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (Example 38 step A) (150 mg, 0.406 mmol, HPLC 1.185 min) and morpholine (707 ul, 8.1 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (157 mg, 92%, HPLC 0.586 min), MS (ISP) m/e=421.2 [(M+H)+].
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O[CH:7]=[C:8]([C:14](=O)[CH:15]([F:17])[F:16])[C:9]([O:11]CC)=[O:10])C.[OH-].[Na+].Cl>C(O)C>[F:16][CH:15]([F:17])[C:14]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 82.9 %

Procedure:
A 400 liter stirred vessel was initially charged with 22.6 kg (172 mol) of methylhydrazine solution (35% by weight of methylhydrazine in water) and 132 kg of ethanol, and cooled to (−55)° C. Within 2.33 hours, at internal temperature from (−50) to (−60)° C., 40.4 kg (172.5 mol) of ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (94.8%) were metered in from a reservoir vessel. The reservoir vessel was rinsed out with 9.1 kg of ethanol. The suspension was stirred at (−55)° C. for a further one hour and then the vessel contents were heated to 25° C. within 4 hours. 102.3 kg (255.75 mol) of 10% sodium hydroxide solution were metered in within 45 minutes, the feed line was rinsed out with 10 liters of demineralized water and the reaction mixture was stirred at 60° C. for 3 hours. After cooling to 25° C., the pressure was reduced stepwise down to 50 mbar. In the course of slow heating to internal temperature 42° C., a total of 180 liters of ethanol/water were distilled off. 300 liters of water were fed and the reaction mixture was cooled to 10° C. At this temperature, 47.8 kg (419 mol) of hydrochloric acid (32%) were metered in within one hour. After the feed line had been rinsed with 10 liters of water, the resulting suspension was stirred at 25° C. for 12 hours. The solids were then filtered off in portions through a pressure filter and the filtercake was washed with 30 liters of demineralized water (with stirring). The solids were substantially freed of liquid by injecting 2.5 bar of nitrogen and, after discharge, dried in a drying cabinet (35-40° C., 25 mbar). After drying, 25.1 kg of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid were obtained in a purity of 99.6% (GC area %). The yield, based on the molar amount of methylhydrazine used, was 82.6%.
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:42])[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[C:21]4[N:22]=[CH:23][CH:24]=[N:25][C:26]=4[C:27]([C:30]4[C:35]([Cl:36])=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=4[Cl:41])=[CH:28][CH:29]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:5]1.[C:43](=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:3][C:4]1([CH3:42])[N:9]([CH3:43])[CH2:8][CH2:7][N:6]([CH2:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[C:21]4[N:22]=[CH:23][CH:24]=[N:25][C:26]=4[C:27]([C:30]4[C:31]([Cl:41])=[C:32]([O:39][CH3:40])[CH:33]=[C:34]([O:37][CH3:38])[C:35]=4[Cl:36])=[CH:28][CH:29]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNC(C)(C)C4)nc3)c3nccnc23)c1Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)C(C)(C)C4)nc3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
Methyl iodide (15 μL, 0.24 mmol, 1.2 equiv) was added to a mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid [6-(3,3-dimethyl-piperazin-1-ylmethyl)pyridin-3-yl]-amide (Example 112) (115 mg, 0.2 mmol) and potassium carbonate (33 mg, 0.24 mmol, 1.2 equiv) in CH3CN (4 mL). The reaction mixture was stirred for 72 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) followed by trituration id Et2O to afford 27 mg of the title compound as a yellow solid. Title compound: ESI-MS: 595.1/596.6 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(#N)C.C(N(CC)CC)C.[CH:34]1[CH:39]=[CH:38][C:37]([O:40][C:41](OC2C=CC=CC=2)=[N:42][C:43]#[N:44])=[CH:36][CH:35]=1>>[C:43](/[N:42]=[C:41](\[O:40][C:37]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1)/[N:7]1[CH2:8][CH2:9][C@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)#[N:44]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 88.2 %

Procedure:
To a stirred solution of (3R,4S)-4-((R)-3-Phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylic acid methyl ester (654 mg, 0.00207 mol) in anhydrous acetonitrile (11.0 mL, 0.211 mol) at rt was added triethylamine (0.579 mL, 0.00413 mol) and diphenyl cyanocarbonimidate (762 mg, 0.00310 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product as a colorless solid (841 mg, 88% in yield). MS (ESI): (M+H)+=461.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH3:24][C@:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]1(C)CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A mixture of (S)-benzyl 3-(tert-butoxycarbonylamino)-3-methylpyrrolidine-1-carboxylate (29.35 g, 87.77 mmol) and 10% Pd/C (4.670 g, 4.388 mmol) in ethanol (50 mL) was charged with hydrogen (1 atmosphere) and stirred at ambient temperature overnight. The catalyst was removed by filtration and washed with ethanol (2×50 mL). The filtrated was concentrated under reduced pressure to give (S)-tert-butyl 3-methylpyrrolidin-3-ylcarbamate (17.13 g, 85.53 mmol, 97.45% yield) as an oil. MS APCI (+) m/z 201 (M+1) detected.