Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N)(=O)[C@H:2]([C@@H:4]([C:6](N)=[O:7])O)O.[C:11]1(O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[C:14]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:6]([OH:7])=[CH:4][CH:2]=[C:1]2[C:13]=1[CH:12]=[CH:11][CH:20]=[CH:19]2
Reactant: NC(=O)[C@@H](O)[C@H](O)C(N)=O
Reactant: Oc1cccc2ccccc12
Product: Oc1ccc2ccccc2c1-c1cccc2ccccc12

Procedure:
On the other hand, 2.7 g of (+)-binaphthol (VII) ([α]D20, +21.0° (C=0.55, tetrahydrofuran)) which was obtained by silica gel chromatography of the filtrate obtained when the clathrate compound was separated and 2.19 g of (-)-(S,S)-tartaric acid diamide (X) were dissolved in the above-described mixed solvent, and thus-obtained solution was allowed to stand for 12 hours at room temperature. The crystallized crystal was recrystallized once to obtain 2.70 g of a clathrate compound (colorless prismatic crystal: mp, 150-151° C.; [α]D20, -43.9° (CHCl3)) containing (-)-tartaric acid diamide (X) and (+)-naphthol (XI) in a ratio of 1 : 1. The obtained crystal was subjected to column chromatography to obtain 1.48 g of (+)-binaphthol (VII) ([α]D20, +36.5° (C=1.3, tetrahydrofuran)).
Reaction SMILES: [CH2:1]([N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])[CH:2]=C.C[N+]1([O-])CC[O:29]CC1.[C:33]([O-:36])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[OH:29][CH:2]([CH2:33][OH:36])[CH2:1][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24]
Reactant: O=C([O-])O
Reactant: C=CCn1c(C#N)c(-c2ccccc2)c2cc(OC)ccc2c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(=O)n(CC(O)CO)c(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 88 (261 mg, 0.83 mmol) was dissolved in 24 mL of acetone and 10 mL of water. OsO4 (Aldrich, 2.5% in 2-Me-2-propanol, 1.04 mL) was added then NMO (116 mg, 1 mmol). The resulting mixture was stir at RT overnight then diluted with 1:1 sat NaHCO3/sat Na2SO3. It was partitioned between EtOAc and aq NaHCO3, then the organic phase was washed once with brine. The combined aqueous phases were washed once with EtOAc. Drying (Na2SO4) and concentration gave the title compound 89 as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCCC1.O>[OH:17][C:7]1([C:5]2[S:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: Cc1cc(C2(O)CCC3(CC2)OCCO3)sn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C2(O)CCC(=O)CC2)sn1
Reaction time: 8 h

Procedure:
8-(3-Methyl-isothiazol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (0.76 g, 0.0030 mol) was dissolved in tetrahydrofuran (10 mL), and a solution of 3.0 M of hydrogen chloride in water (5.0 mL) was added. The mixture was stirred overnight. Solid potassium carbonate was added to neutralize the acid and EtOAc was added to extract the product. The extract was dried and concentrated to give a crude product which was used directly for next step.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[C:50]([O:54][C:55](=[O:58])[CH2:56][Zn+])([CH3:53])([CH3:52])[CH3:51].C(OCC)C>CCOC(C)=O>[C:9]([NH:8][C:5]1[N:6]=[N:7][C:2]([CH2:56][C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:58])=[CH:3][CH:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)nn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1ccc(NC(=O)C(C)(C)C)nn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of N-(6-bromopyridazin-3-yl)pivalamide (2.00 g, 7.75 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.222 g, 0.465 mmol), and tris-dipalladium(dibenzylideneacetone) (0.213 g, 0.232 mmol) was flushed with nitrogen for 30 min. THF (20 mL) was added, followed by a 1.0 M solution of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in diethyl ether (38.7 mL, 19.4 mmol) and the reaction was sealed and stirred for 2 h at 50° C. An additional amount of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (15.5 ml, 7.75 mmol) was added and the mixture stirred for 2 h at 50 C. The resulting mixture was diluted with EtOAc and filtered, then washed with water and brine. The organic layer was dried (sodium sulfate), filtered and concentrated. MPLC (3−>30% EtOAc:Hex) provided title compound. LC-MS (IE, m/z): 294 [M+1]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCCCCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C#CCCCCl)cc1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-iodonitrobenzene (25 g, 100 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.30 g, 0.43 mmol) and copper (I) iodide (0.18 g, 0.95 mmol) in tetrahydrofuran (300 mL) and triethylamine (150 mL) was degassed under Argon for 10 minutes. The mixture was then heated to 55° C. and treated with 5-chloropentyne (12 mL, 110 mmol) via syringe. After 30 minutes of stirring, additional quantities of dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and 5-chloropentyne (1 mL) were added. After another 30 minutes of stirring, the mixture was allowed to cool to room temperature and then was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide 1-(5-chloropent-1-ynyl)-4-nitrobenzene, which was carried on without further purification. ES/MS calcd. for C11H11ClNO2+ 224.1, found m/z=224.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([OH:15])[CH2:10]2.N1C=CC=CC=1.[Cl:22][C:23]([C:33]([F:36])([F:35])[F:34])=[CH:24][C@@H:25]1[C@H:27]([C:28](Cl)=[O:29])[C:26]1([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[Cl:22][C:23]([C:33]([F:34])([F:35])[F:36])=[CH:24][C@@H:25]1[C@H:27]([C:28]([O:15][CH:9]2[CH2:8][C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)=[O:29])[C:26]1([CH3:32])[CH3:31]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3cccs3)c2C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC1Cc2cccc(-c3cccs3)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A stirred solution of 0.54 g (0.003 mole) of 4-(2-thienyl)-2-indanol and 0.25 g (0.003 mole) of pyridine in 15 mL of toluene was cooled to 5° C., and 0.65 g (0.003 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 5 mL of toluene was added dropwise. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 16 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give an oil residue. The oil was subjected to column chromatography on silica gel, eluting with 100% hexane then 1% ethyl acetate-hexane. The appropriate fractions were combined and concentrated under reduced pressure to give 0.57 g of 4-(2-thienyl)-2-indanyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
In 80 ml of dimethylformamide was dissolved 12.22 g of p-hydroxybenzaldehyde, and 17.66 g of anhydrous potassium carbonate and 13.0 ml of benzyl bromide were added to the solution and the mixture was stirred at room temperature in a nitrogen current for 1 hour. After the reaction, water was added to the reaction mixture and the formed precipitate was recovered by filtration and recrystallized from a dichloromethane/hexane mixed solvent to obtain 20.07 g (yield=94.6%) of 4-benzyloxybenzaldehyde in the form of a colorless needle.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[CH2:18]([N:20]=[C:21]=[S:22])[CH3:19]>>[CH2:1]([N:8]1[C:9](=[O:12])[S:10][N:20]([CH2:18][CH3:19])[C:21]1=[S:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=S
Reactant: S=C=NCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CCn1sc(=O)n(Cc2ccccc2)c1=S

Procedure:
Reagents: Benzyl isothiocyanate (0.86 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isothiocyanate (0.57 ml, 6.5 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][NH:10][C@H:9]([C:15]([O:17]C)=[O:16])[CH2:8][C:7]2=1.[OH-].[Na+].[C:21](=[S:23])=[S:22].[CH3:24]I>CO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][N:10]([C:21]([S:23][CH3:24])=[S:22])[C@H:9]([C:15]([OH:17])=[O:16])[CH2:8][C:7]2=1
Reactant: S=C=S
Reactant: CI
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3c(C)cccc23)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC(=S)N1Cc2[nH]c3c(C)cccc3c2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
610 mg of methyl (3S)-8-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate are dissolved in 20 ml of methanol, and 2 ml of a 10% aqueous sodium hydroxide solution are added thereto. The mixture is stirred at room temperature for 3 hours. One ml of a 10% aqueous sodium hydroxide solution and 228 mg of carbon disulfide are added to the mixture, and the mixture is stirred at room temperature for 30 minutes. Then, 355 mg of methyl iodide are adde to the mixture, and the mixture is stirred at the same temperature for 2.5 hours. After the reaction, the mixture is evaporated to remove the solvent. The residue is dissolved in water, and the aqueous solution is extracted with ethyl acetate. The aqueous layer is acidified with 10% HCl, and then extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. A mixture of ether and n-hexane is added to the residue, and the precipitates are collected. 200 mg of (3S)-8 -methyl-2-(methylthio)thiocarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid are obtained as white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(O)CCC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Reactant: Clc1ccn2nccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Fc1ccc(F)c([C@H]2CCCN2c2ccn3nccc3n2)c1
Temperature: 160 °C
Yield: 68 %

Procedure:
In a pressure reaction tube was added 5-chloropyrazolo[1,5-a]pyrimidine (4.2 g, 27 mmol), (R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A; 5.3 g, 29 mmol), anhydrous n-butanol (5 ml, 55 mmol), and DIEA (9.5 ml, 55 mmol). The yellowish suspension was sealed and heated in an oil bath (160° C.) overnight. The reaction was cooled to ambient temperature, diluted with EtOAc (250 mL), and filtered, rinsing the solid with EtOAc. The filtrate (330 mL) was washed with water (2×150 mL), brine (100 mL), concentrated, and purified by silica chromatography, eluting with 2:1 EtOAc/hexanes to give the product as a bright yellowish solid (5.6 g, 68% yield).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@H:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(Cl)(Cl)Cl>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][C@H:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ncccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(C3=CCN(C[C@H]4CCc5ccc6ncccc6c5O4)CC3)c2c1
Yield: 56.6 %

Procedure:
A solution of (6R)-toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.17 g, 0.47 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.20 g, 0.94 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2 hours. The reaction mixture was then poured into chloroform (100 mL) and washed with water (3×40 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (5% methanol/ethyl acetate) afforded 0.11 g (55%) of the title compound. The fumarate salt was prepared in ethyl acetate and isopropyl alcohol and had mp 210° C. and [α]25D=−60.030° (c=4.5, DMSO).
Reaction SMILES: Cl.N[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.C=O.[C:18]([BH3-])#[N:19].[Na+].[C:22](O)(=O)CC>CO>[CH3:22][N:19]([CH3:18])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(=O)O
Reactant: [BH3-]C#N
Reactant: CCOC(=O)CCc1cccc(N)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCc1cccc(N(C)C)c1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 98.5 g (0.43 moles) of ethyl 3-aminobenzenepropanoate hydrochloride in 1500 ml of methanol and 400 ml 37% aqueous formaldehyde (4.3 moles) was added 74 g (1.16 moles) of sodium cyanoborohydride. The reaction was allowed to stir overnight under a nitrogen atmosphere. After 425 ml (5.16 moles) of propionic acid were added, the reaction mixture was refluxed for 4.5 hours. The methanol was evaporated in vacuo and the residue was brought to pH 6.8 by 25% sodium hydroxide addition. The mixture was extracted with diethyl ether which was washed with water, brine solution and dried over anhydrous potassium carbonate. The ether was evaporated in vacuo and the residue was distilled in a Kugelrohr under reduced pressure to give 74.04 g of ethyl 3-dimethylaminobenzenepropanoate, mp 94°-98° C. (oxalate), (72.1% yield).
Reaction SMILES: B.CSC.[C:5]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)(=[O:8])[CH2:6][CH3:7].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]>O1CCCC1>[OH:8][C@@H:5]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH2:6][CH3:7].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: CCC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: B
Agent: c1cc[cH-]c1
Solvent: C1CCOC1
Solvent: CSC
Product: CC[C@@H](O)[c-]1cccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.5 ml (25 mmol) of borane-dimethyl sulphide adduct were added dropwise at 200C to a solution of 10.0 g (41.3 mmol) of propionylferrocene and 2.5 ml (2.5 mmol, 0.06 eq) of catalyst (S)-III (R6 =CH3) in 30 ml of tetrahydrofuran over a period of 30 minutes. After 1 hour at 20°-25° C., the reaction mixture was poured while stirring vigorously onto about 200 ml of ice/water and stirred for 0.5 hours. The aqueous phase was subsequently extracted three times with 200 ml each time of tert-butyl methyl ether, the combined organic phases were dried over magnesium sulphate and evaporated in a high vacuum. This gave 10.7 g (106%) of the crude title compound. This crude product can be used without further purification for the further reactions.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1>CN(C=O)C>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1ccc2ncnc(Cl)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Piperazine (1.1 g, 12.8 mmol) was added to a solution of 4-chloro-6-methoxy-quinazoline (0.5 g, 2.6 mmol) in DMF (5 mL). The mixture was stirred at rt for 1 h, partitioned between chloroform and aq. ammonia. The org. phase was washed with water, dried over MgSO4 and concentrated. Purification by CC (DCM/MeOH 19:1+0.5% NH4OH) gave the desired intermediate (0.57 g, 91%) as yellow oil.
Reaction SMILES: [Mg].II.Br[CH2:5][CH3:6].Cl[C:8]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:9]=1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:16](=[O:17])[O:15][C:14]2(O)[CH3:21].[ClH:31]>C(OCC)C>[Cl:31][C:8]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:9]=1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:16](=[O:17])[O:15][C:14]2([CH2:5][CH3:6])[CH3:21]
Reactant: CCBr
Reactant: Cl
Reactant: CC1(O)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCC1(C)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Reaction time: 0.67 h

Procedure:
Magnesium (1.44 g, 0.06 mol) suspended in diethyl ether (20 ml), was treated with a crystal of iodine, then a solution of bromoethane (6.54 g, 0.06 mol) in diethyl ether (15 ml) was added dropwise over 30 minutes. Reflux was maintained throughout this period by the heat of reaction. The mixture was stirred for 45 minutes before a solution of 5-(2-chloro-4-trifluoromethylphenoxy)-3-hydroxy-3-methylphthalide (5.38 g, 0.015 mol) dissolved in diethyl ether (20 ml) was added over 20 minutes. After stirring for a further 40 minutes, 50% hydrochloric acid (12 ml) was cautiously added, then the phases separated. The organic phase was washed with water 3×15 ml), the solvent stripped off and the residual oil distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](F)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)[C:14](Cl)=[O:15].[CH3:19][O-].[Na+]>C1(C)C=CC=CC=1.CO.CN(C)C=O>[CH3:19][O:6][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([O:15][CH3:14])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: C[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)c(OC)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2-chloro-4,5-difluoro-benzoic acid (15.0 kg, 99 wgt % purity, 77.1 moles, 1.00 eq) and dimethylformamide (0.2 kg, 2.73 moles, 0.04 eq) in toluene (75.9 kg) was treated with oxalyl chloride (19.8 kg, 156.0 moles, 2.02 eq) while maintaining the temperature at <25° C. over 2 hours. The mixture was heated to 50° C. and held 1 hour. At this point, HPLC indicated reaction completion. Remaining oxalyl chloride was removed by distillation, the pot temperature rising from 85 to 110° C. reflecting the removal of the lower boiling oxalyl chloride until only toluene was distilling. The cooled reaction mass (<25° C.) was transferred to another vessel that contained 25 weight % sodium methoxide in methanol (50.5 kg, 233.7 moles, 3.03 eq) in methanol (90.0 kg). The mixture was stirred overnight at 25° C. and monitored by HPLC. The methanol was removed by distillation at 50° C./150 mmHg vacuum while the volume was maintained by the addition of toluene (total of 184.6 kg added). The distillation was continued until the methanol content by GC was 1.16 v/v %. The resulting solution was washed sequentially (each first stirred for 15 minutes) with water (150.0 kg), 1.6 weight % hydrochloric acid (37.0 kg), aqueous sodium bicarbonate (1.85 kg sodium bicarbonate in 33.15 kg water), and water (35.0 kg). The washed solution was filtered through a 0.2 micron cartridge filter and the volume reduced by half by distillation at 50° C./150 mmHg vacuum. The mixture was heated to 80° C. to redissolve the solids that had appeared and heptane (68.0 kg) was added while maintaining the temperature at 70° C. The slurry was cooled to 5° C. and held overnight. The crystals were collected by filtration, washed with heptane (34.0 kg) and dried at 50° C./50 mmHg to yield 14.4 kg (85% yield) of pure 2-chloro-5-fluoro-4-methoxy-benzoic acid methyl ester product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH3:21])[CH3:2].[Br:23]Br.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:17][C:18]([Br:23])=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCCc2cccs2)cc1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(OCCc2ccc(Br)s2)cc1C
Reaction time: 0.25 h

Procedure:
A solution of ethyl[2-methyl-4-(2-thien-2-ylethoxy)phenoxy]acetate (intermediate 69, 0.306 g) in acetic acid (5 ml) was treated with bromine (0.180 g) at ambient temperature and the mixture stirred for 15 minutes. The mixture was poured into water and the resulting suspension extracted with diethyl ether. The organic layer was separated, dried over sodium sulfate and concentrated to give the title compound as a colourless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1>CN(C)C=O>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:31][CH:30]=1
Reactant: ClCc1ccc(COc2ccccn2)cc1
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cnn(Cc3ccc(COc4ccccn4)cc3)c2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2,6-diamine (25 mg, 0.14 mmol) described in Manufacturing Example 36-1-2 in N,N-dimethylformamide (3 mL) was added sodium hydride (8.6 mg, 0.22 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.). Following 30 minutes of stirring at room temperature, 2-(4-chloromethyl-benzyloxy)-pyridine (43.4 mg, 0.19 mmol) described in Manufacturing Example 30-1-1 was added and stirred for 30 minutes at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate only) to obtain the title compound (22.8 mg, 43%).