Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[CH2:18][C:17](=O)[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[OH:24][NH2:25].C([O-])(=O)C.[Na+]>O>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[CH2:18][C:17](=[N:25][OH:24])[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1c(C2CC(=O)CS2)ncn1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(C2CC(=NO)CS2)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene (0.14 g., 0.5 mole) is dissolved in 1 ml. of ethanol and 1 ml. of water is added. Then hydroxyamine hydrochloride (38 mg., 0.55 mole) and sodium acetate (45 mg., 0.55 mole) are added. The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo. The residue is triturated with chloroform and the mixture is filtered. The chloroform extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude oxime, 2-(1-benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene oxime, is a brown viscous oil (0.15 g.).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH:22]=C)=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:8]1.CSC>ClCCl>[CH3:4][O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH:22]=[O:1])=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:8]1
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(N3C[C@H](COC)OC3=O)noc2c1
Solvent: ClCCl
Solvent: CSC
Product: COC[C@H]1CN(c2noc3cc(C=O)ccc23)C(=O)O1
Reaction time: 3 h

Procedure:
A stream of ozone at -40° C. is passed for 2 hours into a solution of 8.0 g (0.029 mol) of (R)-5-(methoxymethyl)-3-(6-ethenyl-1,2-benzisoxazol-3-yl)oxazolidin-2-one in 210 ml of dichloromethane, then the ozone is driven off with a stream of argon, and 10.7 ml (0.15 mol) of dimethyl sulphide are added. The mixture is stirred for 3 hours while allowing the temperature to return to ambient temperature, and then the solvent is evaporated off under reduced pressure. By chromatography of the residue on a silica column with a mixture of 30% ethyl acetate in cyclohexane, 5.0 g of product are obtained.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1.Cl>CN1C(=O)CCC1>[CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(N)c3)nc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(NS(C)(=O)=O)c3)nc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
45 mg of the product from example 5-1 were dissolved in 1 ml dry NMP and cooled to 0° C. 18.3 mg methylsulfonylchloride were added and the mixture was stirred for 1 hr at 0° C. and another hr at room temperature. 12 μl (1 equivalent) pyridine were added and stirring was continued for another 60 min. After addition of 0.1 ml conc. HCl, the solvent was removed under vacuum and the residue purified by chromatography on C-18 RP silica in methanol water mixtures.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.C([Mg]Cl)(C)C.C[CH2:18][S:19](=S)([O-])=O>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([S:19][CH3:18])=[CH:3][S:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CCS(=O)([O-])=S
Reactant: Clc1ncnc2scc(Br)c12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1csc2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 127.7 %

Procedure:
5-bromo-4-chlorothieno[2,3-d]pyrimidine (750 mg, 3.0 mmol) was partially dissolved in anh. THF (8 mL), cooled to 0° C. and treated in portions with a 2M THF solution of i-PrMgCl (2.0 mL, 4.0 mmol). After 20 minutes, this solution was treated dropwise with methylmethanethiosulfonate (460 μl, 570 mg, 4.5 mmol). The cooling bath was removed and the mixture was stirred for 4 hours at 25° C. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4) and evaporated to give 830 mg crude product-ca 80 percent pure by GC. The material was purified by recrystallization from hot heptane to give 350 mg (45 percent) yield of tan crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Cl:16][C:17]1[N:22]=[CH:21][C:20](I)=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>C1COCC1.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:16][C:17]1[N:22]=[CH:21][C:20]([C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:15])=[CH:12][CH:11]=2)=[CH:19][N:18]=1
Reactant: Clc1ncc(I)cn1
Reactant: C#Cc1ccc(C(C)C(=O)NCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(C)c1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1.10 g (5.46 mmol) N-ethyl-2-(4-ethynyl-phenyl)-propionamide (XVII.1) in 10 mL THF are added 1.31 g (5.46 mmol) 2-chloro-5-iodo-pyrimidine under argon, followed by 0.42 g (0.60 mmol) Pd(PPh3)2Cl2 as catalyst, 57 mg (0.30 mmol) copper(I)iodide and 2.1 mL (12 mmol) DIPEA as base. The mixture is stirred at rt for 4 h. After that time, the mixture is filtered and the solvent is evaporated from the filtrate. The residue is purified by column chromatography (silicia gel; DCM:MeOH gradient 1:0/1:1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH:21]([C:25](O)=[O:26])[CH2:22]3)=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:32]#[N:33].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[C:32]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([CH:21]2[CH2:22][C:23]3[CH:24]=[C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]=4)[CH:16]=[CH:17][C:18]=3[CH2:19][CH2:20]2)=[O:26])[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(C#N)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of 7-{[2-(tert-butoxycarbonyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.653 g, 1.77 mmol), 3-amino-5-(trifluoromethyl)-benzonitrile (0.362 g, 1.94 mmol), and DMAP (0.238 g, 1.94 mmol) in DCM (10 mL) was cooled to 0° C. To this solution was added EDCI (0.339 g, 1.77 mmol). The reaction mixture was allowed to stir and warm to rt overnight. The reaction mixture was diluted with EtOAc, washed with 1N HCl and sat. aq. NaHCO3, and concentrated. The residue was purified by column chromatography to give tert-butyl 4-{[7-({[3-cyano-5-(trifluoromethyl)phenyl]-amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylate (0.750 g, 79%). LCMS: (FA) ES+ 538.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][CH2:9]2)=[CH:5][C:4]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([S:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[C:20]#[N:21]>>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([C:19]([S:32][C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([OH:12])[CH:5]=3)[CH2:9]2)[C:20]#[N:21])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(C(C#N)(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1O)CNC2
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Yield: 74.2 %

Procedure:
The procedure of Example 49 is used with 0.209 g of 2,3-dihydro-6-methoxy-1H-isoindol-5-ol (Example 105) and 0.57 g of α-(5-bromopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile. This affords 0.5 g of the desired product as a gray foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1)=[O:9].[H-].[Na+].[CH3:27]I>CN(C)C=O>[CH3:27][N:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=2)[N:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: CI
Reactant: O=C(Nc1cnccn1)Nc1ccnc2ccc(C(F)(F)F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)Nc1ccnc2ccc(C(F)(F)F)cc12)c1cnccn1
Reaction time: 16 h
Yield: 21.2 %

Procedure:
A solution of 145 mg (0.44 mmol) of 1-pyrazin-2-yl-3-(6-trifluoromethyl-quinolin-4-yl)-urea (Example 14) and 16 mg (0.65 mmol) of sodium hydride in 10 ml of dimethylformamide was stirred at 0° C. for 10 min. Methyl iodide (93 mg, 0.65 mmol) was added and the solution was allowed to reach RT and stirred for a further 16 h. The solution was concentrated in vacuo, and partitioned between dichloromethane and water. The organic layer was washed 3 times with water, concentrated in vacuo and the material purified by chromatography. White solid. Amount 32 mg. Yield 21.2%.
Reaction SMILES: [CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:45])/[C:14](/[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)=[C:15](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:16][CH2:17][O:18][Si](C(C)C)(C(C)C)C(C)C)=[CH:8][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:46][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:45])/[C:14](/[C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=2)=[C:15](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:16][CH2:17][OH:18])=[CH:10][CH:11]=1
Reactant: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(/CCO[Si](C(C)C)(C(C)C)C(C)C)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(/CCO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5f (95 mg, 0.147 mmol) in THF (2 ml) was added a 1M solution of tetrabutylammonium fluoride (0.18 ml) in THF under ice cooling, and the mixture was stirred at room temperature for 30 min. H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by silica gel flash column chromatography (eluent: AcOEt to CHCl3/MeOH, 5:1) gave 5 g (90%). 5 g: colorless oil; 1H-NMR (CDCl3) δ 2.74 (2H, t, J=5.7 Hz), 3.02 (2H, t, J=5.6 Hz), 3.43 (3H, s), 3.63 (2H, t, J=5.6 Hz), 4.06 (2H, t, J=5.7 Hz), 5.09 (2H, s), 6.79 (2H, d, J=8.3 Hz), 6.88 (2H, d, J=9.1 Hz), 6.99 (2H, d, J=8.6 Hz), 7.09 (2H, m), 7.16-7.21 (3H, m), 7.45 (2H, d, J=8.8 Hz), 7.82 (1H, brs).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-])=O.O>CO.[Fe]>[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH3:11]
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 2-nitro-4-chlorotoluene (86 g, 0.5 mol) in MeOH (250 mL) was added Fe powder (92 g, 3.65 mol) by portions over 45 min while refluxing gently. The mixture was stirred for 3 h at room temperature, poured into water (1.5 L) and extracted with AcOEt. The organic layers were dried over MgSO4 and concentrated in vacuo to give 63 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-methylquinoline (1.63 g, 11.4 mmol) in dry THF (10 mL), cooled by ice/water, is added phenyllithium (1.9M in cyclohexane/ether 70/30, 6.0 mL, 11.4 mmol) dropwise over 5 min. After 15 min, the cooling bath is removed, and the solution is stirred at rt for 5 h. The reaction is quenched by adding MeOH, and stirring is continued overnight. Water is added, the mixture is extracted with EtOAc (3×35 mL), and the combined extracts are dried over MgSO4. The drying agent is filtered off, and air is bubbled into the solution for 7 d. The solvent is evaporated; the residue is dissolved in warm (≈50° C.) EtOAc/hexanes and filtered warm. The filtrate is concentrated and dried in vacuo to obtain the crude title compound that is used directly for the next step. Further purification is possible by chromatography on silica gel (Jones Flashmaster, eluting with hexanes: EtOAc 3:1→2:1→1:1). 1H NMR(CDCl3, 400MHz) δ 2.58 (s, 3H), 7.31 (d, J=3.7 Hz, 1H), 7.36-7.49 (m, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.96 (s, 1H), 8.16 (t, J=8.0 Hz, 2H). MS (ES+): m/z 220.3 (100) [MH+]. HPLC: tR=2.7 min (Platform II, nonpolar—5 min).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([C:9](=[O:11])[CH3:10])[C:5]([CH:12]=[CH2:13])=[CH:4][N:3]=1.[CH2:14]([Mg]Br)[CH3:15]>O1CCCC1>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([C:9]([OH:11])([CH2:14][CH3:15])[CH3:10])[C:5]([CH:12]=[CH2:13])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(C)c(O)c1C(C)=O
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: C=Cc1cnc(C)c(O)c1C(C)(O)CC
Reaction time: 48 h

Procedure:
A solution of 3.93 g. of the product from Step A in 200 ml. of tetrahydrofuran was treated dropwise with 110% excess of ethyl magnesium bromide in tetrahydrofuran. After aging 2 days at ambient temperature the reaction was quenched on ice-water (100 ml.) containing 10 g. of ammonium chloride. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give 2-methyl-3-hydroxy-4-(2-hydroxybut-2-yl)-5-vinylpyridine, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18][C:19]1[O:20][CH2:21][CH2:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[O:20][CH2:21][CH2:22][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)C1=C(N)OCC1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)OCC1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 2-amino-4,5-dihydrofuran-3-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[3-(ethoxycarbonyl)-4,5-dihydro-furan-2-yl]ureido}-benzoate.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1>O>[Cl:3][CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1
Reactant: O=S(Cl)Cl
Reactant: O=c1c2ccccc2ncn1CCO
Solvent: O
Product: O=c1c2ccccc2ncn1CCCl
Temperature: 85 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
This thionyl chloride (1,095 mL, 15 mmol) was added to 3-(2-hydroxyethyl)quinazoline-4(3H)-one (2.0 g, 10.52 mmol) in a reactor, forming a white suspension that heated spontaneously to 85° C. The reaction medium was kept at this temperature under agitation for thirty minutes, after which it was left to cool to about 40° C. Next, 50 mL of water was added, forming a pinkish suspension, which was kept under agitation for two hours. The product was then vacuum filtered and washed with three portions of 10 mL of an ethanol/water mixture (50% v/v), yielding 3-(2-chloroethyl)quinazoline-4(3H)-one as a pale white solid (1.8 g, 8.63 mmol, yield=82%).
Reaction SMILES: [CH:1]([C:13]([O:15]C)=O)([C:9]([O:11]C)=O)[CH2:2][CH2:3][C:4]([O:6][CH2:7]C)=[O:5].[C:17]1(/[CH:23]=[CH:24]/[C:25](=[NH:27])[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>CO>[OH:15][C:13]1[N:26]=[C:25](/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:27][C:9](=[O:11])[C:1]=1[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: N=C(N)/C=C/c1ccccc1
Reactant: CCOC(=O)CCC(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1c(O)nc(/C=C/c2ccccc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Ethyl 1,1-dimethyl 1,1,3-propanetricarboxylate (23.8 g; 103 mmol) and (2E)-3-phenyl-2-propenimidamide (10.0 g; 68.4 mmol) were combined in MeOH (400 mL), treated with NaOMe in MeOH (31.0 g; 143 mmol) and the solution was stirred at room temperature for 2 days. The solution turned dark, and a dark green solid was filtered off. The solution was concentrated under vacuum, diluted with water, acidified to pH 2 with 6N HCl and the resulting yellow precipitate was filtered off. The aqueous mother liquor was extracted with EtOAc. During the extraction more yellow precipitate formed and was collected. The combined yellow solids were dried under vacuum and used without further purification (12.1 g, 59%).
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:9][CH:8]=1)([O-])=[O:5]>[Rh].O1CCCC1>[OH:5][NH:4][C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Rh]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(NO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrazine hydrate (containing 55% hydrazine, 1.5 mL, 26.25 mmol, 1.05 equiv.) was added dropwise over 1 minute to a mixture containing benzyl 4-nitrobenzoate (Brewster, J. H.; Ciotti, C. J., Jr. J. Am. Chem. Soc. 1955, 77, 6214; 6.43 g, 25 mmole, 1 equiv.), 5% rhodium on carbon (wet, 625 mg), and tetrahydrofuran (50 ml) at 0° C. under argon. When the addition was complete, the mixture was warmed to room temperature, stirred for 4 hours, and then was filtered through Celite®. Concentration of the filtrate gave crude benzyl 4-(hydroxyamino)benzoate as a yellow oil which was used without further purification. Pure benzyl 4-(hydroxyamino)benzoate, obtained from a separate preparation by silica gel chromatography (30% ethyl acetate/toluene) was used for characterization purposes: TLC(30% ethyl acetate/toluene) Rf 0.52; 1H NMR (250 MHz, CDCl3) δ 7.99 (d, J=8.6 Hz, 2 H), 7.26-7.55 (m, 5 H), 6.97 (d, J=8.6 Hz, 2H), 5.33 (s, 2H); IR (CHCl3) 3550, 3315, 1703, 1606, 1273, 1169, 1101, 693 cm-1 ; MS(DC/NH3) 261.2 (M+NH4)+, 245.2 (M+MH4 -16)+, 228.1 (M+H-16)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:26])([F:25])[F:24])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].Cl.C[N:29](C)CCCN=C=NCC.CN(C)C=O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:25])([F:26])[F:24])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:29])=[O:21])=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (2.50 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.89 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.38 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (2.23 g, yield 89%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point >300° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:16]([CH:13]1[CH2:15][CH2:14]1)[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: NC1CC1
Solvent: CO
Product: O=C1c2ccc(Br)cc2CN1C1CC1
Yield: 85.7 %

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (1A2) (1.62 mmol, 500 mg) and cyclopropylamine (1A3) (3.25 mmol, 185 mg) in methanol (3 ml) were heated in the microwave at 120° C. for 10 mins. The reaction mixture was concentrated and purified on silica eluting with 50-100% EtOAc/heptane to yield 5-bromo-2-cyclopropylisoindolin-1-one (1A4) 350 mg (84%); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, 1H) 7.59 (d, 1H) 7.78 (s, 1H) 4.30 (s, 2H) 2.91 (m, 1H) 0.94-0.85 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CN(C)C=O.O>[CH3:11][O:10][C:8]1[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:9]=1
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Ex-29C: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde from Ex-29B (0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Once at 80° C., 1-bromo-2-(2-methoxyethoxy)ethane (0.24 g, 1.3 mmol) was added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers was sequentially washed with a saturated ammonium chloride solution (1×15 mL), water (1×15 mL), and brine (1×15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 4:1) afforded 0.13 g (87%) of 4-methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehyde as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H), 7.30 (dd, 1H), 7.07 (dd, 1H), 6.57 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.94 (t, 2H), 3.74 m, 2H), 3.59 (m, 2H), 3.40 (s, 3H). HRMS (EI) Calcd. for C17H20O5S: 336.1031. Found: 336.1027.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][NH:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.O>ClCCl>[Si:5]([O:13][CH2:12][CH2:11][NH:10][CH3:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CNCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyldimethylchlorosilane (4.2 g, 27.9 mmol) in dichloromethane (10 mL) was added dropwise over 3 min to a stirred solution of 2-(methylamino)ethanol (2.0 g, 26.6 mmol) and imidazole in dichloromethane (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane then the combined organic phases were passed through a phase separation cartridge and the solvent removed under reduced pressure to afford a colorless oil (5.10 g, 95%). This was taken through to the next step with no further purification.