Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:21][C@H:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:19][O:18][CH2:17][CH2:16]1.NO.[CH2:32]([N:34](CC)CC)[CH3:33].C(OC(=O)C)(=[O:41])C>C(O)C.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:21][C@H:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]3[N:34]=[C:32]([CH3:33])[O:41][N:27]=3)=[CH:24][CH:23]=2)[CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(N2CCOC[C@@H](c3ccc(C#N)cc3)C2)nc(-c2ccncn2)cc1=O
Agent: NO
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc([C@@H]3COCCN(c4nc(-c5ccncn5)cc(=O)n4C)C3)cc2)no1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-4-(4-(1,6-dihydro-1-methyl-6-oxo-4-(pyrimidin-4-yl)pyrimidin-2-yl)-[1,4]oxazepan-6-yl)benzonitrile (183 mg, 0.471 mmol) in ethanol (0.95 ml) was added 50 wt. %—hydroxylamine aqueous solution (96.4 mg, 1.46 mmol) at room temperature. The mixture was stirred at 80° C. for 2 hours and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. N,N-dimethylformamide (0.95 ml), triethylamine (143 mg, 1.41 mmol) and acetic anhydride (62.5 mg, 0.612 mmol) was added to the residue at 0° C. The mixture was stirred at room temperature. After 2 hours, the mixture was heated to 135° C. and stirred for 2 hours. The resulting mixture cooled to room temperature was partitioned between water and chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to afford (S)-3-methyl-2-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-[1,4]oxazepan-4-yl)-6-(pyrimidin-4-yl)pyrimidin-4(3H)-one (A085) as white solid (126 mg, 60%).
Reaction SMILES: [CH:1]1([P:4](Cl)(Cl)=[O:5])[CH2:3][CH2:2]1.[CH:8]([Mg]Br)=[CH2:9].[NH4+].[Cl-].[CH2:14]1COC[CH2:15]1>>[CH:1]1([P:4](=[O:5])([CH:8]=[CH2:9])[CH:14]=[CH2:15])[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: C=C[Mg]Br
Reactant: O=P(Cl)(Cl)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CP(=O)(C=C)C1CC1
Temperature: -78 °C
Reaction time: 7 h
Yield: 39 %

Procedure:
To a 250 mL round-bottom flask equipped with a magnetic stir-bar was added cyclopropyl phosphonic dichloride (2.33 g, 14.7 mmol) and THF (100 mL). The solution was cooled to −78° C. and vinylmagnesium bromide (58.8 mmol, 1.0 M solution in THF) was added dropwise over 15 minutes. The solution was stirred at −78° C. for 7 hours and then poured, while still cold, into saturated aqueous NH4Cl (200 mL). The resulting solution was extracted with DCM (3×100 mL). The organic layers were combined, washed with brine (2×100 mL), dried over sodium sulfate and concentrated in vacuo to provide cyclopropyl-divinyl-phosphine oxide (0.811 g, 39%) as a light-brown free-flowing oil which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 6.40-6.00 (m, 6H), 0.98-0.80 (m, 5H); GC-CIMS (m/z): (M+1)+ found, 142.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[C:9]1[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([NH2:25])=[O:24])[C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2]2.[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29].C12NC(CC1)CC(=[C:41]1[C:54]3[CH:53]=CC=C(O)[C:49]=3[O:48][C:47]3C1=CC=CC=3)C2>>[O:48]1[CH:47]=[CH:41][C:54]([CH2:53][N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][C:3](=[C:9]2[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([NH2:25])=[O:24])[C:17]=4[O:16][C:15]4[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:2]3)=[CH:49]1.[C:28]([OH:30])([C:27]([F:32])([F:31])[F:26])=[O:29]
Reactant: NC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2
Reactant: O=C([O-])C(F)(F)F
Reactant: Oc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2
Product: NC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2Cc1ccoc1
Product: O=C(O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 9-(8-azabicyclo[3.2.1 ]oct-3-ylidene)-9H-xanthene-4-carboxylic acid amide for the trifluoroacetate salt of compound 2, the title compound 4 was obtained as a TFA salt.
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.[CH3:20][C:21]1[C:26](=[O:27])[C:25]2[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([Cl:34])=[O:33])[C:24]=2[O:23][C:22]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[OH-].[Na+].O>ClCCCl.ClCCl>[ClH:34].[ClH:34].[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:6][CH2:5][N:4]([CH2:3][C:2]([CH3:19])([O:1][C:32]([C:31]2[C:24]3[O:23][C:22]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[C:21]([CH3:20])[C:26](=[O:27])[C:25]=3[CH:28]=[CH:29][CH:30]=2)=[O:33])[CH3:18])[CH2:9][CH2:8]1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Reactant: COc1ccccc1N1CCN(CC(C)(C)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC(C)(C)OC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl
Temperature: 25 °C
Yield: 111.4 %

Procedure:
5.29 g of Intermediate XXVIII in 25 ml of 1,2-dichloroethane was added dropwise at 60° C. to a solution of 6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 22 ml of 1,2-dichloroethane. The reaction mixture was refluxed for 16 hours, and then cooled to ambient temperature and poured into cold 0.5N aqueous sodium hydroxide solution. Water and dichloromethane were added. The organic phase was separated off, washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents were evaporated off and the oily residue was purified by flash chromatography on silica gel, eluting with petroleum ether:ethyl acetate (85:15). The collected fractions were evaporated to dryness in vacuo and the residue was dissolved in ethanol. Excess ethanolic hydrogen chloride was added to give 6.71 g of the title compound, m.p. 203°-204° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH3:24]>CN(C=O)C>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH2:23][CH3:24])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCn1c(=Nc2ccc(C)cc2)sc2ncccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a mixture of 900 mg (3.34 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 15 ml of DMF was added 27 mg of lithium hydride in a stream of argon, and it was stirred for 30 minutes at room temperature. To the mixture was then added 568 mg of n-propyl iodide. The mixture was then stirred for 2 hours. After the termination of the reaction, the mixture was concentrated under reduced pressure. To the resulting residue was added water and ethyl acetate, and extracted. The resulting organic phase was separated, washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 584 mg of 2,3-dihydro-2-[(4-methylphenyl)imino)-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ether and hexane) as a low polarity substance and 179 mg of 2-[N-(4-methylphenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([NH2:15])=[C:9]([CH2:16][CH3:17])[CH:8]=[C:4]1[C:5]([OH:7])=O.[CH3:18]C(C)=O.ClC(OCC)=O.[CH:28]1([N:35]2[CH2:39][CH2:38][CH2:37][C:36]2(C)[CH2:40][NH2:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O.Cl.C(N(CC)CC)C>[CH:28]1([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH:40]([CH3:18])[NH:41][C:5](=[O:7])[C:4]2[CH:3]([O:2][CH3:1])[C:11](=[S:12](=[O:14])=[O:13])[C:10]([NH2:15])=[C:9]([CH2:16][CH3:17])[CH:8]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC1(CN)CCCN1C1CCCCCC1
Reactant: CCC1=C(N)C(=S(=O)=O)C(OC)C(C(=O)O)=C1
Reactant: CC(C)=O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC1=C(N)C(=S(=O)=O)C(OC)C(C(=O)NC(C)C2CCCN2C2CCCCCC2)=C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.9 g of 2methoxy-4-amino-5-ethyl sulphonyl benzoic acid, 57 ml of acetone, 10 ml of water and 2.6 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The solution is cooled to between 0° and +5° C. and 2.1 g of ethyl chloroformate is added drop by drop. The reaction medium is agitated for 45 minutes at room temperature then cooled to 0° C. and 5.3 g of 1-cycloheptyl methyl-2-amino methyl pyrrolidine is poured in drop by drop. The medium is agitated for 4 hours then left to stand overnight. The solvents are evaported to dryness and the residue is dissolved in 60 ml of water and 15 ml of hydrochloric acid (density 1.18). Extraction is carried out 3 times with 50 ml of methylene chloride, the organic phase is dried over magnesium sulphate and filtered, and the solvent is evaporated under vacuum. The residue is dissolved in 100 ml of water. The solution is filtered in the presence of carbon black and the filtrate is made alkaline with about 7 ml of ammonia (density 0.91). A gum is precipitated. It is extracted 3 times with 50 ml of methylene chloride. The organic phase is washed twice with 50 ml of water, dried over magnesium sulphate and filtered. The solvent is evaporated under vacuum and the residue is re-crystallized in 100 ml of isopropanol.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26](OC)OC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CN(C=O)C>C1C=CC=CC=1>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][CH:24]1[O:25][CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1OC(OC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 103 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (1.16 mmol) was suspended in benzene (10 ml), and trimethoxymethane (3.44 mmol) and PPTS (72 mg) were added. Heating to reflux (103° C.) did not dissolve the starting compound. 2 ml of DMF were then added so that most of the starting compound dissolved, although the solution remained somewhat turbid. The flask was equipped with a Soxhlet extractor. The thimble of the extractor was filled with 4 Å mol. sieves. After 1 hour, and approximately 3 to 4 cycles in the Soxhlet extractor, TLC showed consumption of the starting material, and a new major spot of the title product. It was diluted with EtOAc, washed with NaHCO3 and H2O, dried and the solvent removed. NMR showed the presence of the title product and a small impurity. The product was purified on HPLC (hexane:ethyl acetate, 3:1) to give 358 mg (87%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]([N:9]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)[CH2:14][CH2:13]2)[CH3:10])=[O:8])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7](=[O:8])[N:9]([CH3:10])[CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]#[C:19][CH2:20][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CO
Product: CN(C[C@H]1CC[C@H](C#CCN2CCCCC2)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 222 mg (corresponds to 0.40 mmol) of crude trans-methanesulfonic acid 3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-prop-2-ynyl ester in 4 ml of methanol was cooled to 0° C., treated with 0.34 ml (4 mmol) of piperidine and stirred over night at room temperature. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/ether (3×). The organic phase was dried with sodium sulfate, filtered and evaporated. Purification by flash column chromatography on silica gel (methylenechloride/methanol 99:1 to 98:2) gave 92 mg (57%) of pure trans-methyl-[4-(3-piperidin-1-yl-prop-1-ynyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 403 (MH+, 1Cl). The following compounds were prepared from the corresponding mesylates and secondary amines:
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:10][C:11]1[C:12]([I:25])=[C:13]([C:22]([OH:24])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17].O>CC(N(C)C)=O>[C:1]([O:4][C@@H:5]([CH3:9])[C:6]([NH:10][C:11]1[C:19]([I:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([I:21])=[C:13]([C:12]=1[I:25])[C:22]([OH:24])=[O:23])=[O:7])(=[O:3])[CH3:2]
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
(S)-1-chloro-1-oxopropan-2-yl acetate (0.75 ml, 5.91 mmol) was added drop-wise to a solution of 5-amino-2,4,6-triiodoisophthalic acid (1.0 g, 1.79 mmol) in DMA (5 ml). The resulting mixture was stirred at about 50° C. for 5 hours and 20 minutes. 80 ml of water was added to the reaction mixture at room temperature after which the suspension formed was cooled to a temperature between 0° C. and 5° C. and stirred for 25 minutes at this temperature. The suspension was filtered and the solid washed with water. The product was dried in a vacuum oven at 40° C. to yield (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid (0.695 g, 1.03 mmol). The MS, 1H-NMR and 13C-NMR data are consistent with the structure for (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH3:13]
Reactant: Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)cc(C)cc1[N+](=O)[O-]
Yield: 97.9 %

Procedure:
2-Bromo-4-methyl-6-nitro-phenol 11b (22.24 g, 95.9 mmol) was dissolved in 150 mL of acetone, followed by addition of potassium carbonate (15.9 g, 115 mmol) and iodomethane (13.7 mL, 220.6 mmol). The reaction mixture was heated to reflux overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate and filtered. The mixture was concentrated under reduced pressure to obtain the title compound 1-bromo-2-methoxy-5-methyl-3-nitro-benzene 11c (23.1 g, yield 97.9%) as an orange solid.
Reaction SMILES: Br[C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]([CH2:15][CH3:16])[N:5]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:15]([CH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:14][C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:3][C:4]=2[N:5]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:16]
Reactant: OB(O)c1ccccc1
Reactant: CCC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(OC)cc1
Product: CCC1c2ccccc2-c2sc(-c3ccccc3)cc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 38.6 %

Procedure:
Starting from 2-bromo-5-ethyl-4-[(4-methoxyphenyl)sulfonyl]-4,5-dihydrothieno[3,2-c]isoquinoline (1.02 g, 2.2 mmol) and substituting phenylboronic acid (0.35 g, 2.9 mmol) in place of 3-thiopheneboronic acid in Step 1, the title compound (0.38 g, 50%, m.p. ° C.) was synthesized in essentially the same manner as described in Example 8, Steps 1-2, for 4-[(5-ethyl-2-thien-3-ylthieno[3,2-c]isoquinolin-4(H)-yl)sulfonyl]phenol.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Cl.[OH-].[Na+]>O>[CH2:1]([NH:8][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CCl)OC
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(CNCc1ccccc1)OC
Temperature: 27.5 °C
Reaction time: 0.21 h

Procedure:
Benzylamine (0.927 kg), chloroacetaldehydedimethylacetal (0.909 kg), sodium hydroxide solution (0.35 kg) in 2.72 L of water were charged into the flask under stirring at 25-30° C. for 10-15 min. Reaction mass was heated to 100-102° C. under stirring for 30 hrs. After completion of reaction, reaction mass was allowed to settle for 30 min. Two layers are separated and upper product layer was collected, distilled under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH2:23])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>>[NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH:23][C:37]([NH:36][C:27]4[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=4[F:25])=[O:38])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Nc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Nc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c4ccccc34)c2[nH]c1=O
Yield: 38 %

Procedure:
Method F2 was used with 3-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a yellow/orange solid (31 mg, 38%).
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>CN(C)C=O.O>[Cl:42][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CO)cc32)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CCl)cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
A solution of 6-hydroxymethyl-1-(4-methylphenylsulfonyl)indole (21.0 g) and triphenylphospine (21 g) in a mixture of N,N-dimethylformamide (200 ml) and carbon tetrachloride (27 ml) was stirred at room temperature for 18 hr under a nitrogen atmosphere. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4), and evaporated to give 6-chloromethyl-1-(4-methylphenylsulfonyl)indole (21.4 g, 96%) as an ivory solid partial NMR (80 MHz, CDCl3): 2.34 (s, 3H, ArCH3), 4.71(s, 2H, ClCH2), 6.62(dd, 1H, H3 -indole), 8.02(m, 1H, H7 -indole). f. 1-(4-Methylphenylsulfonyl)indole-6-acetonitrile.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)=[O:5].[CH3:13][OH:14]>>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([O:14][CH3:13])[CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: CO
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Product: COC(=O)c1cc(OC)ccn1
Yield: 88 %

Procedure:
4-Chloropyridine-2-carboxylic acid methyl ester hydrochloride (25 g, 0.12 mol) was dissolved in methanol (200 ml) and heated at reflux for 66 h. The solvent was evaporated and the residue partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over sodium sulphate and concentrated to give 4-methoxypyridine-2-carboxylic acid methyl ester (17.6 g, 88%) as a yellow crystalline solid. 1H NMR (360 MHz, CDCl3) δH 3.91 (3H, s), 4.02 (3H, s), 6.98 (1H, dd, J 3 and 6), 7.67 (1H, d, J 3), 8.54 (1H, d, J 6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:25])[CH2:13][CH2:14][C:15]1([C:21](OC)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.Br[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:13][CH2:14][C:15]3([CH2:20][CH2:19][N:18]([CH2:29][CH2:30][O:31][C:32]4[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=4)[CH2:17][CH2:16]3)[C:21](=[O:22])[O:25]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: COC(=O)C1(CCC(O)c2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Reactant: Fc1cc(F)cc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2ncc(Cl)c(C3CCC4(CCN(CCOc5cc(F)cc(F)c5)CC4)C(=O)O3)c2c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 83.6 %

Procedure:
A mixture of 1 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidine-4-carboxylate, 0.8 g of 1-(2-bromoethoxy)-3,5-difluorobenzene and 0.42 g of potassium carbonate in 45 cm3 of acetonitrile was maintained at a temperature of 80° C. with stirring and under an argon atmosphere for 20 hours. The suspension was filtered, the insoluble material was washed with ethyl acetate and the filtrate was then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue was purified by chromatography under a pressure of 100 kPa of argon, on a column of silica gel (particle size 40-60μ; diameter 3.5 cm; height: 38 cm), eluting with a dichloromethane/methanol mixture (97/4 by volume) and collecting 35-cm3 fractions. Fractions 9 to 20 were combined and then concentrated to dryness under the above conditions. 1.1 g of 3-(3-chloro-6-methoxyquinolin-4-yl)-9-[2-(3,5-difluorophenoxy)ethyl]-2-oxa-9-azaspiro[5.5]undecan-1-one were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:23])([NH2:22])[CH3:21])=[CH:15][C:14]=1[F:24].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:22][C:20]([CH3:23])([CH3:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([F:24])[CH:15]=1
Reactant: CC(C)(N)Cc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 90 °C
Reaction time: 38.5 h
Yield: 57.2 %

Procedure:
A mixture of 3-chloro-4-fluoro-1-nitrobenzene (421 mg, 2.40 mmol) and 1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-amine (484 mg, 2.40 mmol) in DMSO (10 mL) was heated at 90° C. under N2 for 3 h. The mixture was cooled to rt and stirred at rt for 38.5 h. It was then heated and stirred further at 90° C. for 81.5 h. The mixture was cooled to rt and 80 mL of water was added. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 (10 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=20:1) to give the title compound as yellow oil (490 mg, 57.2%). The compound was characterized by the following spectroscopic data: