Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1)(=O)[CH3:2].C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[CH3:2][C:1]1[C:8]2[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][N:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CC(=O)NCCc1cn(-c2ccccc2)c2ccccc12
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC1=NCCc2c1n(-c1ccccc1)c1ccccc21

Procedure:
A mixture of 40.8 g. N-acetyl-1-phenyltryptamine (IIIa), 800 ml. dry benzene and 220 g. phosphorus oxychloride is refluxed for 1 hour. After cooling, the reaction mixture is poured into two liters of cold water with continued stirring and cooling for 1.5 hours. The organic layer is separated, washed twice with water and the aqueous fractions combined and backwashed once with ethyl acetate. The aqueous extract (total volume 3 liters) is treated with one liter of 10% NaOH, followed by one liter of 50% NaOH while stirring and cooling in an ice bath. The product precipitates from the cooled solution and is filtered and washed well with water to remove any co-precipitated inorganic material. Upon drying, 34 g. of 4,9-dihydro-1-methyl-9-phenyl-3H-pyrido[3,4-b]indole, (IVa), m.p. 110°-112° C. is obtained. An analytical sample had a m.p. 110°-112° C. (benzene-petroleum ether).
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[C:3]([N+:9]([O-:11])=[O:10])=[N:4][CH:5]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1CCN(c2cc(Cl)cnc2[N+](=O)[O-])CC1
Temperature: 50 °C
Yield: 59.8 %

Procedure:
A mixture of 3,5-dichloro-2-nitropyridine (193 mg, 1.00 mmol), 4-methylpiperidine (118 μL, 1.00 mmol) and K2CO3 (138 mg, 1.00 mmol) in toluene (10 mL) was heated at 50° C. for 3 h. Toluene was removed in vacuo and the residue obtained was purified on silica (2% EtOAc/hexane) to obtain the title compound (153 mg, 60%). 1H-NMR (CDCl3; 400 MHz): δ 7.95 (s, 1H, J=2.5 Hz), 7.58 (s, 1H, J=2.5 Hz), 3.30 (m, 2H), 2.95 (m, 2H), 1.87 (m; 2H), 1.65 (m, 1H), 1.35 (m, 2H), 1.0 (d, 3H, J=6.3 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1CCC(O)=O)([O-:3])=[O:2].[Na:18].C(=O)([O-])O.[Na+].NC1C=C(N)C=CC=1[O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30]>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30])([O-:3])=[O:2].[Na:18]
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(Oc1ccc(N)cc1N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: CC(Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O

Procedure:
The 2-(2,4-dinitrophenoxy)-propionic acid from step (a) was converted into the sodium salt with sodium hydrogen carbonate and reduced in aqueous solution, using procedures analogous to those set forth in A, and the sodium salt was then isolated. Five grams of 2-(2,4-dinitrophenoxy)-propionic acid yielded 2.4 gm of sodium salt of 2-(2,4-diaminophenoxy)-propionic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25](O)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:51][C:52]1([F:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([N:55]1[CH2:56][CH2:57][C:52]([F:58])([F:51])[CH2:53][CH2:54]1)=[O:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCc3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.8 %

Procedure:
To the solution of 2.3 g (6.2 mmol) 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester (intermediate G), 2.5 g (7.8 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 1.2 g (7.8 mmol) 4,4-difluoropiperidine hydrochloride in 30 ml DMF, 6.4 ml (4.8 g, 37.4 mmol) N,N-diisopropylethylamine were added. After 40 min. stirring at room temperature the clear solution was poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic layers were washed three times with water and with brine, dried over magnesium sulfate, filtered and evaporated. The residue was re-crystallized from dichloromethane and n-heptane to give 2.8 g (95%) of the desired compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH2:21][NH2:22].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CCC>[NH:21]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1)[NH2:22]
Reactant: COc1cc(-c2ccc(Cl)nn2)ccc1OC(F)F
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1cc(-c2ccc(NN)nn2)ccc1OC(F)F
Temperature: 80 °C
Yield: 93.4 %

Procedure:
20.0 g (69.8 mmol) of 3-chloro-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine are boiled under reflux in 100 ml of n-butanol with 17 ml (350 mmol) of hydrazine hydrate for 8 hours. The solution is cooled to about 80° C. and stirred with 100 ml of saturated sodium carbonate solution and 200 ml of water. The precipitate is filtered off with suction, washed with water and dried in vacuo. 18.4 g (93.4%) of 3-hydrazino-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine of m.p. 154° C. are obtained.
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][CH:16]([OH:18])[CH3:17].N>C(O)(=O)C>[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[CH2:15][CH:16]([OH:18])[CH3:17]
Reactant: CC(O)Cn1ccc2c(O)cccc21
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(O)CN1CCc2c(O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
1.4 g of sodium cyanoborohydride were added to a solution of 7 g of 4-hydroxy-1-N-(β-hydroxypropyl)indole, obtained in the preceding stage, in 40 cm3 of acetic acid, the temperature being maintained below 30° C. After stirring for 30 minutes, the reaction mixture was poured onto 200 g of ice-cold water and the pH was neutralized to 7.5 by addition of 30% aqueous ammonia. The precipitate obtained was filtered off and dried. 4 g of the expected product were obtained, the melting point of which was between 130° and 131° C. and the elemental analysis of which, calculated for C11H15NO2, was as follows:
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][C@H:15]4[O:31][C:32](=[O:40])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=C[C@H]4O)CC2)C)OC1>>[O:29]1[C@H:20]2[C@H:19]([OH:30])[CH2:18][C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)[C@H:15]([O:31][C:32](=[O:40])[NH:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:16]=3
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(=O)Nc4ccccc4)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(=O)Nc4ccccc4)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 62.6 %

Procedure:
The procedure of Example 36 was repeated except that 2.8 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-phenylcarbamoyloxy)pregn-5-en-3β-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol to give 1.5 mg of 1α,2α-epoxy-3β-hydroxy-7α-(N-phenylcarbamoyloxy)pregn-5-ene-20-carbaldehyde (yield: 63%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][N:14]([CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:9]([O:11]C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.[OH-].[Li+]>O>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][N:14]([CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:9]([OH:11])=[O:10])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCCCN(C[C@@H](C(=O)OC)C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCCCN(C[C@@H](C(=O)O)C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.7 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)-propanoate iv (500 mg, 1.06 mmol) was dissolved in the mixed solvent system: THF (4 mL), methanol (1 mL), and water (2 mL). Powdered lithium hydroxide (250 mg, 10.4 mmol) was added. The light yellow slurry was stirred at rt for 15 h, and then concentrated in vacuo. The residue was partitioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1 N HCl until the pH was 4. This acidic solution was extracted with ethyl acetate four times. The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to give 430 mg (89%) of (S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid v as a yellow oil. 1H NMR (CD3OD, 300 MHz) δ 1.38 (s, 9H), 1.51–1.60 (m, 2H), 1.89–1.98 (m, 2H), 3.28–3.32 (m, 2H), 3.59–3.64 (dd, J=14.95, 9.46 Hz, 1H), 3.71–3.74 (m, 1H), 4.33 (dd, J=9.61, 4.43 Hz, 1H), 4.87–4.94 (m, 2H), 5.63–5.72 (m, 1H), 7.71–7.77 (m, 3H), 8.01 (dd, J=7.48, 1.37 Hz, 1H). LC-MS (Method D, retention time: 2.04 min), MS m/z 358 (M++1-Boc).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CS(O)(=O)=O.[CH2:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:16]1[O:18][CH2:17]1>>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:9][CH2:17][CH:16]([OH:18])[CH2:15][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCO
Reactant: CCCCCCCCOCC1CO1
Agent: CS(=O)(=O)O
Product: CCCCCCCCOCC(O)COCCCCCCCC
Temperature: 95 °C
Yield: 7 %

Procedure:
Octyl alcohol (11.7 g; 0.09 mol) and methanesulfonic acid (0.50 g; 5.50 mmol) were placed in a 100-ml four-necked flask and heated up to 95° C. while stirring them under nitrogen. Octyl glycidyl ether (17.1 g; 0.09 mol) was then added dropwise over 10 minutes, and the resultant mixture was stirred for 8 hours as it was. After completion of the reaction, the reaction mixture was washed with a 4N aqueous solution (40 ml) of sodium hydroxide and additionally twice with water (40 ml) and then purified by column chromatography on silica gel (developing solvent: hexane) to obtain 2.0 g of 1,3-dioctyl glyceryl ether (9,13-dioxa-11-heneicosanol) as a colorless transparent oil (yield: 7%).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8]O)[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1(C)C=CC=CC=1>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:4][CH2:3]1
Reactant: OCC1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(CC1CCC(F)(F)CC1)C(=O)OC(C)(C)C
Temperature: 12.5 °C
Yield: 113.1 %

Procedure:
To 3.9 g of (4,4-difluorocyclohexyl)methanol was added 40 mL of toluene. 10.2 g of triphenylphosphine was added thereto at room temperature, followed by stirring for a while. The mixture was ice-cooled, and 7.2 g of di-tert-butyl azodicarboxylate was portionwise added thereto while maintaining the internal temperature at about 10 to 15° C. The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 10.7 g of di-tert-butyl 1-[(4,4-difluorocyclohexyl)methyl]hydrazine-1,2-dicarboxylate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH2:24]>>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH:24][C:9](=[O:11])[CH2:8][N:3]1[C:4](=[O:7])[CH2:5][CH2:6][CH:2]1[CH3:1]
Reactant: CCOC(=O)CN1C(=O)CCC1C
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: CC1CCC(=O)N1CC(=O)NCCN1[C@H](C)CCC[C@@H]1C

Procedure:
From 9.26 g. of ethyl 2-methyl-5-oxo-1-pyrrolidineacetate (British Pat. No. 1,309,692) and 8.6 g. of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine, following the procedure of Example 9, there is obtained cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-methyl-5-oxo-1-pyrrolidineacetamide; m.p. 115°-116° C. after crystallization from cyclohexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[CH:22]3)[C:16]([CH2:29][CH3:30])=[C:15]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:43]=[C:44]=O)(=O)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:44]#[N:43])[C:16]([CH2:29][CH3:30])=[C:15]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc3c(ccn3C)c2)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Yield: 79.1 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-5-ethyl-6-(1-methyl-1H-indol-5-yl)nicotinate (880 mg, 1.74 mmol) in DMF (10 mL) was added chlorosulfonyl isocyanate (0.18 mL, 2.07 mmol, 1.2 eq) at 0° C. The reaction was monitored by LC-MS and starting material was completely consumed within 5 min. The reaction was quenched with water then extracted by CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4 and then concentrated to give a crude product which was purified by trituration with hexanes and CH2Cl2 to afford the title compound (732 mg, 79%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:10]1[CH:9]=[CH:8][C:7]([Cl:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cccc(Cl)c1-c1ccccc1Cl
Product: C=CCc1ccc(Cl)c(-c2ccccc2Cl)c1O
Yield: 77 %

Procedure:
A solution of 2-allyloxy-2′,6-dichlorobiphenyl (11.6 g, 41.8 mmol) in mesitylene (100 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 9.0 g (77%) of 3-allyl-2′,6-dichlorobiphenyl-2-ol as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.CO[Na]>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:21])[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:7]2=[O:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccn1
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Br)cc2C(=O)C1c1ccccn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 5-bromo-2-[2-(pyridin-2-yl)acetamido]benzoate (3 g, 7.73 mmol, Intermediate 9: step a) and MeONa (11.7 mL, 31 mmol, 2.64 M in MeOH) in tetrahydrofuran (30 mL). The resulting solution was stirred overnight at 20° C. Then, the solvents were removed by a rotary evaporator and 50 mL water was added to the residue. The pH of the resulting mixture was adjusted to 7 with 1 M aqueous HCl. The solid was collected by filtration and dried under vacuum to afford the title compound as a white solid which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([C:13]4[C:33]([F:34])=[CH:32][C:16]5[NH:17][C:18]([O:20][CH:21]6[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]6)=[N:19][C:15]=5[C:14]=4[F:35])=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.O([Si](C)(C)C)[K]>C1COCC1.CCOC(C)=O>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([C:13]4[C:33]([F:34])=[CH:32][C:16]5[NH:17][C:18]([O:20][CH:21]6[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]6)=[N:19][C:15]=5[C:14]=4[F:35])=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3[nH]2)CC1
Agent: C[Si](C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-{[5-(1-cyclopropyl-1H-indol-5-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.046 g, 0.96 mmol) was dissolved in 1 mL of THF and treated with 37 mg of KOTMS (0.037 g, 0.288 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was then diluted with EtOAc and washed with 2 N HCl. The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. LCMS: calculated for C25H23F2N3O3 451.46, observed m/e 451.92 (MAI)+ (Rt 2.42/4 min). 1H NMR (500 MHz, CD3OD): δ7.62 (d, 1H), 7.56 (brs, 1H), 7.25-7.20 (m, 2H), 7.00-6.92 (br, 1H), 6.42 (d, 1H), 4.92 (m, 1H), 3.41 (m, 1H), 2.37 (m, 1H), 2.34-2.27 (m, 2H), 2.15-2.07 (m, 2H), 1.73-1.55 (m, 4H), 1.13-1.08 (m, 2H), 1.03-0.98 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([OH:17])[C:3]=1[N:18]1[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[O:35][S:36]([CH3:39])(=[O:38])=[O:37].C([O-])([O-])=O.[Na+].[Na+].Cl>COCCOC.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>[CH2:27]([O:17][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[N:18]1[CH2:19][C:20](=[O:25])[NH:21][S:22]1(=[O:23])=[O:24])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[O:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(CBr)c(OS(C)(=O)=O)c1
Reactant: CC1(C)OB(c2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc(Cc2cc(F)c(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c(OS(C)(=O)=O)c1
Temperature: 60 °C

Procedure:
A mixture of 5-[2-fluoro-6-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (150 mg, 0.325 mmol) and Pd(PPh3)4 (38 mg, 0.0325 mmol) in DME (2 mL) is heated at 60° C. under argon for 1 h. Then methanesulfonic acid 2-bromomethyl-5-methylphenyl ester (181 mg, 0.65 mmol) and Na2CO3 (2N solution, 0.81 mL) is added. The mixture is heated at 120° C. in a microwave for 20 min. 1N HCl is added and the reaction mixture is extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4 and filtered. The filtrate is concentrated to give the title compound and it is used directly in the next step: MS (M−H)−=533.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:5][CH:6]=1.[CH3:13][Si:14]([CH2:17][CH3:18])([CH3:16])[CH3:15]>>[CH2:7]([C:4]1[S:3][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:6][CH:5]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC[Si](C)(C)C
Reactant: CCCCCCc1ccc(Br)s1
Product: CCCCCCc1ccc(C#C[Si](C)(C)C)s1
Yield: 101.1 %

Procedure:
According to the method described in S117a, 2-bromo-5-hexylthiophene (1 g, 4 mmol) was reacted with trimethylsilylethane (0.43 g, 4.4 mmol) to give the title compound as a yellow oil (1.07 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.05 (d, 1H, J=3.6 Hz), 6.61 (d, 1H, J=3.6 Hz), 2.77 (t, 2H, J=7.2 Hz) 1.65-1.56 (m, 2H), 1.36-1.30 (m, 6H), 0.89 (t, 3H, J=6.4 Hz), 0.24 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]#[N:18])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17](=[S:26])[NH2:18])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCCc2ccc(-c3ccccc3)nc21
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)C1CCCc2ccc(-c3ccccc3)nc21
Reaction time: 12 h

Procedure:
2-Phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2 g.) was dissolved in pyridine (5 ml.) and triethylamine (1.3 ml.) and the solution treated with H2S gas for 6 hours and the reaction mixture allowed to stand at room temperature for 12 hours. The solvent was removed and the residual oil dissolved in dilute HCl, extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was made basic and extracted into chloroform (3 × 50 ml.). The combined extracts were dried and evaporated in vacuo to give 2-phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide which was dissolved in ethanol (5 ml.), diluted with ether (25 ml.) and the solution saturated with HCl gas. The solvent was removed in vacuo and the residual solid recrystallised from methanol-ether giving hydrochloride of the title compound as colourless needles mpt. 211° C. Found: C, 63.41; H, 5.70; N, 8.94%. C16H16N2S. HCl requires: C, 63.04; H, 5.62; N, 9.19 %.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)CCC>>[O:37]1[CH:38]=[CH:39][CH:40]=[C:36]1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccco1
Yield: 40 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and tributyl(furan-2-yl) stannane using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a yellow solid (40% yield); 1H-NMR (CDCl3) 1.26 (9H, s), 3.77 (2H, m), 4.16 (2H, m), 6.14 (1H, d), 6.33 (1H, m), 6.35 (1H, s), 7.35 (1H, d); 13C-NMR (d6-DMSO); 27.4, 41.1, 66.6, 104.0, 110.8, 132.2, 141.0; MS ES(+) 252.1 (M++1); HRMS m/z calcd for C13H17NO4+H+ 252.1236 [M+H+]. Found 252.1066. IR λmax=1693 cm−1.