Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([I+:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[CH2:26]([O:28][C:29]1[C:30]2[C:35]([C:36]([O:47][CH2:48][CH3:49])=[C:37]3[C:42]=1[CH:41]=[C:40]([S:43]([OH:46])(=[O:45])=[O:44])[CH:39]=[CH:38]3)=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27].[K]>>[CH2:26]([O:28][C:29]1[C:30]2[C:35]([C:36]([O:47][CH2:48][CH3:49])=[C:37]3[C:42]=1[CH:41]=[C:40]([S:43]([O-:46])(=[O:44])=[O:45])[CH:39]=[CH:38]3)=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27].[C:22]([C:19]1[CH:20]=[CH:21][C:16]([I+:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOc1c2ccccc2c(OCC)c2cc(S(=O)(=O)O)ccc12
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: [K]
Product: CCOc1c2ccccc2c(OCC)c2cc(S(=O)(=O)[O-])ccc12

Procedure:
Preparation of bis(4-t-butylphenyl)iodonium 9,10-diethoxyanthracene-2-sulfonate according to Formula 2 above wherein R3 and R4 are both t-butyl and OR5 and OR6 are both ethoxy is as follows. A slurry of 399 g potassium periodate (1.86 M) was prepared in a pre-made solution of 761 g (705 mL, 7.45 M) acetic anhydride in 500 g (577 mL, 3.725 M) of t-butylbenzene using mechanical stirring. While cooling with ice bath, 402 g (4.1 M) of concentrated H2SO4 was added slowly, maintaining the temperature at 25±5° C. (approximately 2 hours). The reaction was allowed to stir overnight, allowing ice to melt in bath. The next day the reaction was re-cooled to 0-10° C. and a total of 1.25 L H2O added. Initially the reaction was very exothermic, but as the addition proceeded the water was added more rapidly. 252 mL of ammonium hydroxide was added next, followed by 1.5 L dichloromethane. The water layer was discarded, and the dichloromethane layer washed several times with water. The dichloromethane layer was dried with magnesium sulfate and filtered, then evaporated to a low volume on a rotary evaporate to induce crystallization. The solid was filtered and rinsed with toluene and sucked dry. The residue was recrystallized from IPA to yield 243 g of a white solid of bis(4-t-butylphenyl)iodonium acetate. The bis(4-t-butylphenyl)iodonium acetate may then be combined under suitable conditions known in the art with 9,10-diethoxyanthracene-2-sulfonic acid, potassium salt to yield bis(4-t-butylphenyl)iodonium 9,10-diethoxyanthracene-2-sulfonate. Alternatively, 9,10-dimethoxyanthracene-2-sulfonic acid, potassium salt may be used to yield a sulfonium salt according to Formula 2 wherein OR5 and OR6 are both methoxy.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([O:53][CH3:54])[C:39]=1[OH:55]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([O:53][CH3:54])[C:39]([OH:55])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 17.8 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (77 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (17 mg, 18% over 2 steps) as a orange-yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.38 (s, 1H), 8.31 (dd, J=8.8, 1.9 Hz, 1H), 8.25 (m, 2H), 8.05 (d, J=8.8 Hz, 1H), 7.89 (dd, J=9.3, 2.6 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.06 (dd, J=9.3, 0.8 Hz, 1H), 6.90 (s, 1H), 4.15 (dt, J=11.2, 5.7 Hz, 1H), 4.04 (dd, J=11.9, 6.5 Hz, 1H), 3.94 (s, 3H), 3.86 (m, 1H), 3.76 (m, 2H), 2.83 (dt, J=12.1, 6.3 Hz, 1H), 2.60 (dt, J=21.4, 6.6 Hz, 1H), 2.31 (td, J=13.4, 5.7 Hz, 1H), 1.21 (m, 4H); ESI MS m/z 529 [C29H28ClN5O3+H]+; HPLC 99.6% (AUC), tR=9.97 min.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:5]=1.[CH3:19]I>O1CCCC1>[CH3:19][S:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:5]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccccc1Cc1n[nH]c(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cc2ccccc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.61 g of sodium hydride in 50 ml of tetrahydrofuran, 5 g of 5-mercapto-3-(o-nitrobenzyl)-1,2,4-triazole is added in portions with stirring at room temperature over a period of 30 minutes. The mixture is stirred for 2 hours, 1.51 ml of methyl iodide is added at once, the mixture is stirred overnight at room temperature and evaporated to dryness in vacuo. The residue is treated with water and methylene chloride, the aqueous layer is extracted once more with methylene chloride, the combined organic extracts are dried over magnesium sulfate, evaporated to a small volume and diluted with ether to give 5-methylmercapto-3-(o-nitrobenzyl)-1,2,4-triazole, m.p. 120°-132°.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:20])([CH3:1])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:12])=[O:4]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CCCNCCC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCN(CCC)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.1 μL dipropylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 60-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.16 min. (m/Z=290.1, 374.2, 396.1).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([CH:25]3[CH2:34][CH:26]3[CH2:27][O:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18]>CN1C(=O)CCC1.O>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([CH:25]3[CH2:34][CH:26]3[CH2:27][O:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:2]
Reactant: CCN(CC)CCCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 32.9 %

Procedure:
3-Diethylaminopropyl amine (0.975 g) was added to a solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 67, 0.091 g) in NMP (3 mL) and the mixture was heated at 140° C. in a sealed tube for 36 hours. After cooling, the mixture was diluted with water (2 mL) and the solution was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-[2-(3-diethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.039 g) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=O.Cl.[NH2:16]O.S([O-])([O-])(=O)=O.[Mg+2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][CH2:2][Cl:1])[CH:5]=2)[NH:9][CH:8]=1)#[N:16]
Reactant: NO
Reactant: O=Cc1c[nH]c2ccc(CCCl)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2ccc(CCCl)cc12
Temperature: 150 °C
Yield: 95.3 %

Procedure:
A mixture of 3.29 g (15.8 mmol) 5-(2-chloroethyl)indole-3-carboxaldehyde (reference example 5), 1.15 g (16.6 mmol) hydroxylamine hydrochloride, 6.27 g (52.1 mmol) magnesium sulfate, and 0.601 g (3.16 mmol) p-toluenesulfonic acid monohydrate in 10 mL DMF is heated to 150° C. for 30 minutes. The reaction mixture is azeotroped with toluene, and the resulting residue chromatographed (2:1, then 1:1 hexane:ethyl acetate) to provide 3.08 g of product as a white solid in 95% yield. 1H NMR (CDCl3): δ 3.20 (2H, t, J=7 Hz), 3.77 (2H, t, J=7 Hz), 7.21 (1H, dd, J=8, 1 Hz), 7.43 (1H, d, J=8 Hz), 7.63 (1H, s), 7.73 (1H, d, J=3 Hz), 8.66 (1H, br). MS (EI) m/z 204, 206 (M[35Cl, 37Cl])+, 155 (M−CH2Cl)+.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:38][CH2:39][CH3:40])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([N:17]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:41])=[O:5])[C:9]([CH2:38][CH2:39][CH3:40])=[N:10][C:11]=3[CH:16]=2)(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: CCCc1nc2cc(N(CCCOc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(CCCOc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(4-Fluoro-benzenesulfonyl)-(3-phenoxy-propyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.62 (m, 2H), 7.30 (m, 6H), 6.88 (m, 4H), 4.62 (s, 2H), 3.99 (t, 2H), 3.74 (t, 2H), 2.71 (m, 2H), 1.71 (m, 4H), 0.99 (t, 3H). MS calculated for C27H26FN3O5S—H: 524, observed: 524.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[C:19]([CH3:28])[N:18]=1>>[CH2:26]([N:23]([CH2:24][CH3:25])[C:21]1[CH:20]=[C:19]([CH3:28])[N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1)[CH3:27]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CCN(CC)c1cc(C)nc(Cl)n1
Product: CCN(CC)c1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 65 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (67 mg, 0.33 mmol) and (2-chloro-6-methyl-pyrimidin-4-yl)-diethyl-amine (67 mg, 0.33 mmol) in analogous manner as described in example 90. It was obtained in 65% yield as a light yellow viscous oil. MS ISP (m/e): 367.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.15 (s, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.32 (d, 1H), 7.16 (d, 1H), 7.01 (s, 1H), 6.00 (s, 1H), 3.78 (s, 3H), 3.51 (br q, 4H), 2.20 (s, 3H), 2.14 (s, 3H), 1.13 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1>C1(C)C=CC=CC=1.[Ni]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c(N)c(Cl)n1

Procedure:
The third intermediate, 4,6-dichloro-2-methyl-5-nitropyrimidine is hydrogenated over Raney-Ni as a 10% to 30% solution in toluene to afford the corresponding compound, 4,6-dichloro-2-methyl-5-aminopyrimidine, as a fourth intermediate.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>>[CH3:16][C:17]([CH3:22])=[CH:18][C:19]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:20]
Reactant: CC(C)=CC(=O)Cl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Product: CC(C)=CC(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 57.8 %

Procedure:
The procedure of Example 16 was repeated using 1.95 g of 3-phenylindoline and 1.5 g of 3,3-dimethylacryloyl chloride. In this way 1.6 g of the desired N-(3,3-dimethylacryloyl)-3-phenylindoline having a melting point of 97°-8° C was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:30][CH:31]4[CH2:35][CH2:34][CH2:33][O:32]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: OCC1CCCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCO3)cc2)cc1
Yield: 62.6 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo [b]thiophen-3-yl](4-hydroxyphenyl)methanone (390 mg, 1 mmol) and 2-hydroxymethyl tetrahydrofuran (153 mg, 1.50 mmol) were converted to 297 mg of the title compound by the procedure of Example 9 using 393 mg (31.5 mmol) of triphenylphosphine and 0.24 mL (1.5 mmol) of diethyl azodicarboxylate the only differences being that the chromatography eluent was 3:7 ethyl acetate:hexanes.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:34])([C@@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:31])([F:30])[F:29])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:33])[C:19](=[O:32])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:33][C@H:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([C@H:12]([C:10]2([CH3:34])[CH2:9][NH:8][CH2:11]2)[CH3:13])=[C:27]([C:28]([F:29])([F:31])[F:30])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:32]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@@H](C)C4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a solution of 3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 1, 0.062 g, 0.128 mmol) in DCM (4 mL) was added TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give (R)-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #147-1, Enantiomer 1, 0.060 g, 94%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.46 (s, 1H), 7 (s, 1H), 4.95 (m, 1H), 4.70 (d, J=13.2 Hz, 2H), 4.3 (d, J=10.8 Hz, 1H), 3.95 (d, J=10.8 Hz, 1H), 3.65 (t, J=10.0 Hz, 2H), 3.26 (m, 1H), 1.55 (s, 3H), 1.49 (d, J=7.2 Hz, 3H), 1.44 (d, J=7.2 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.741 min; MS m/z: 383 [M+H]+. SFC (Table 1, Method 36) Rt=4.264 min.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Cl[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: ClCc1cccs1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccs1)OCC
Temperature: 150 °C

Procedure:
Following the general procedure for carrying out the Arbuzov reaction (reference cite: Chem. Rev. 81, 415, 1981) 0.1 mole (17.5 ml) of triethyl phosphite and 0.1 mole (13.2 g) of 2-chloromethylthiophene were combined and heated under N2 at 150° C. for 5 hours. The reaction mixture was cooled and partitioned between 100 ml methylene chloride and 50 ml. water. The organic phase was separated, washed with saturated NaHCO3 solution, dried over magnesium sulfate and concentrated under vacuum to yield 17.5 g. crude liquid product.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([I:1])=[CH:12][N:11]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ncc1I
Temperature: 80 °C
Reaction time: 6 h
Yield: 38.2 %

Procedure:
N-iodosuccinimide (15.75 g, 70 mmol) was added to a solution of 2-chloropyridin-4-amine (9.00 g, 70 mmol) in N,N′-dimethylformamide (140 mL) and the mixture was stirred at 80° C. for 6 hours. Further N-iodosuccinimide (7.80 g, 35 mmol) was added and the mixture was stirred at 60° C. overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium thiosulphate, water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (6:1 to 2:1 hexanes/ethyl acetate) to yield the title compound (6.80 g, 38%) as a beige solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]([CH3:32])([CH3:31])[O:28][C:29](=[O:30])[C:24]=2[CH:23]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:34]=[CH:33][C:25]4[O:26][C:27]([CH3:31])([CH3:32])[O:28][C:29](=[O:30])[C:24]=4[CH:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-[(4-butylphenyl)-ethynyl]benzaldehyde and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (purification by flash chromatography on SiO2, EtOAc/c-Hex 15/85) as a yellowish solid (53%). 1H NMR (CDCl3) δ: 7.45 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.15-7.06 (m, 3H), 6.80-6.70 (m, 2H), 4.20 (s, 2H), 4.04 (brs, 1H), 2.57 (t, J=7.7 Hz, 2H), 1.65 (s, 6H), 1.61-1.49 (m, 2H), 1.37-1.23 (m, 2H), 0.88 (t, J=7.3 Hz, 3H). HPLC, Rt: 6.3 min (purity: 92.2%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:35])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:37]1[N:42]=[CH:41][N:40]=[C:39]2[N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[N:44]=[CH:45][C:38]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:35][C:37]1[N:42]=[CH:41][N:40]=[C:39]2[N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[N:44]=[CH:45][C:38]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
Sodium hydride (91 mg, 2.27 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(pyridin-2-yl)propanamide (Intermediate AQ4) (480 mg, 1.03 mmol) (intermediate 3) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (320 mg, 1.14 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane to afford the product (682 mg, 95%). 1H NMR: (400 MHz, CDCl3) δ 0.98-1.00 (9H, m), 3.69-3.72 (2H, m), 3.81 (2H, t), 4.16-4.25 (2H, m), 6.06-6.09 (1H, m), 7.04-7.07 (1H, m), 7.31-7.66 (14H, m), 7.68-7.73 (1H, m), 8.24-8.28 (2H, m), 8.38 (1H, s), 8.58 (1H, s), 8.75 (1H, s); m/z (ES+) M+=693.61; HPLC tR=3.79 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][Na]>CO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:14][CH3:13])=[N:3][C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: CO[Na]
Solvent: CO
Product: COc1nc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask containing 4,7-dichlorquinazoline (250 mg, 0.91 mmol) equipped with a reflux condenser was evacuated and refilled with Ar several times. MeONa (2 mL, 25% wt in MeOH, 8.7 mmol) and anh. MeOH (20 mL) were added and the reaction mixture was heated to reflux under Ar for 5 h. The reaction was cooled to rt and stored at rt overnight then partitioned between DCM (80 mL) and H2O (10 mL). The aqueous layer was extracted with DCM (1×). The combined organics were washed (brine), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.55-8.62 (m, 2H), 8.08 (d, J=9.2 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.52-7.48 (m, 3H), 7.45 (dd, J=2.0 Hz, 8.8 Hz, 1H), 4.28 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>>[CH3:12][C:8]1([CH3:13])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:15](=[O:16])[CH3:14])[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc2c(s1)C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (40.5 g, 0.206 mol) and Ac2O (400 mL) are heated at 100° C. for 4 h. After cooling to RT, the reaction mixture is concentrated in vacuo. The precipitated solid is collected by filtration and affords N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (36.5 g, 75% yield).