Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:11]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:32][CH:33]=4)=[CH:25][CH:24]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58](O)=[O:59])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[C:42]([O:41][C:39]([N:35]1[CH2:36][CH2:37][CH2:38][C@H:34]1[C:31]1[NH:32][CH:33]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:11]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:15][CH:14]=4)[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:58]([C@H:54]5[CH2:55][CH2:56][CH2:57][N:53]5[C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])=[O:59])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[CH:24][CH:25]=2)[N:30]=1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(C2CCC(c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)N2c2ccc(C(C)(C)C)cc2)cc1
Yield: 58.6 %

Procedure:
The product from Example 40D (1.3 g, 2.146 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.386 g, 6.44 mmol), HATU (1.305 g, 3.43 mmol) and Hunig's base (1.124 mL, 6.44 mmol) in DMSO (20 mL) was reacted according to the procedure in Example 39H to provide the title compound (1.01 g, 59%) as a mixture of stereoisomers.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([CH3:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].O.[C:11]([O:14]CC)(=[O:13])[CH3:12]>>[CH3:9][C:6]1[O:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:12]/[C:11]([OH:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(C)o1
Reactant: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)/C=C/C(=O)O)o1

Procedure:
10 g of 2-acetyl 5-methyl furan (J. Am. Chem. Soc., 72 3695 (1950)), 7.4 g monohydrated glyoxylic acid and 5 cm3 water are heated to 120°-130° C. for 5 hours, while eliminating the water formed in the course of the reaction. After cooling, 60 cm3 ethyl acetate are added and extracted with a solution of sodium carbonate. The aqueous phase is acidified, extracted with ethyl acetate, dried, and concentrated to dryness. The residue is chromtographed on silica, then, the product is recrystallized in ethyl acetate. 2.2 g of the expected product are obtained. MP=159°-162° C.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1

Procedure:
The starting tetrahydroisoquinolines of the formula (A), wherein Y is an appropriately substituted 7-benzeneaminosulfonyl radical, are conveniently prepared by standard reactions well known in the chemical arts as shown below: ##STR4## 2-Acetyl-1,2,3,4-tetrahydroisoquinoline was treated with chlorosulfonic acid to yield 2-acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline which is then reacted with an appropriately substituted aniline followed by treatment with dilute mineral acid to give the appropriately substituted tetrahydroisoquinoline (B). The starting tetrahydroisoquinolines of the formula (A), wherein Y is not a 7-benzeneaminosulfonyl radical, are conveniently prepared by standard reactions well known to the chemical arts.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][C:11]=1[Cl:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[C:11]([Cl:17])[CH:12]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)cc1Cl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2)cc1Cl
Yield: 96 %

Procedure:
In accordance with Example 11-(1), but using tert-butyl[(2-chloro-4-iodobenzyl)oxy]dimethylsilane instead of 4-bromobenzyl bromide, and (4-bromophenyl)boronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, the title compound (yield 96%) was afforded as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])=[N:12][O:11][N:10]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:13]2[C:9]([CH2:8][CH2:7][CH2:6][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:10][O:11][N:12]=2)=[O:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CS(=O)(=O)OCCCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Temperature: 70 °C
Yield: 54.2 %

Procedure:
3-(4-[(3-Chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propyl methanesulfonate (19 mg, 0.051 mmol) was dissolved in anhydrous ACN (100 μL,) followed by the addition of DIPEA (44 μL, 0.26 mmol) and morpholine (6.7 μL, 76.8 μmol). The reaction were stirred and heated at 70° C. for 3 h. The reaction was concentrated and purified by silica gel chromatography (60-100% ethyl acetate/hexanes) to give the desired product (10.2 mg, 54%). LCMS for C16H19ClFN4O3 (M+H)+: m/z=369.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].[CH2:15](OC(OCC)OCC)C>>[CH3:13][O:12][C:10]1[C:6]2[C:7](=[O:9])[O:8][CH:15]=[N:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Reactant: CCOC(OCC)OCC
Product: COc1cc(OC)c2c(=O)ocnc2c1
Temperature: 140 °C
Yield: 76.2 %

Procedure:
A mixture of 1.0 g (5.07 mmol) of 4,6-dimethoxy-anthranilic acid, as prepared in Example 3, and 15 ml of triethylorthoformate (90.2 mmol) was heated to 140° C. for 4 h. The volatiles were evaporated under reduced pressure to give 0.8 g of 5,7-dimethoxy-3,1-benzoxazine-4-one as a yellow solid (76% yield), which was used without any further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C@@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@](C)(CO)C5)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
The compound (280 mg, 0.55 mmol) obtained in Example 33-1) was dissolved in methanol (3 mL). A 4 N solution (1.37 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (50 mL) and methanol (2 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (175 mg, 81%) in a colorless solid form.
Reaction SMILES: [O:1]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[N:26]O)=[CH:18][C:17]=1[CH3:28]>P(=O)(O)(O)O>[F:15][C:16]1[C:17]([CH3:28])=[CH:18][C:19]2=[CH:20][CH2:21][CH2:22][C:23](=[O:1])[N:26]=[C:24]2[CH:25]=1
Reactant: Cc1cc2c(cc1F)C(=NO)CCC2
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=P(O)(O)O
Product: Cc1cc2c(cc1F)=NC(=O)CCC=2
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To 70 ml of 85% phosphoric acid, 100 g of phosphoric anhydride were added in portions. After the phosphoric anhydride was dissolved thoroughly, 10.0 g of 7-fluoro-6 -methyl-1-tetralone oxime were added to the resulting solution over 20 minutes at an external temperature of 90° C., followed by stirring for 4 hours under the same conditions. After the completion of the reaction, the reaction mixture was poured into ice water. The crystals so precipitated were collected by filtration. The crystals so obtained were recrystallized from chloroform-diethyl ether, whereby 8.3 g of the title compound was obtained.
Reaction SMILES: C([O:3][C:4](=[O:45])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:7][C:6]=1[O:42][CH2:43][CH3:44])C.[Li+].[OH-]>C1COCC1.CO>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:18][N:14]2[C:12](=[O:13])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:45])=[O:3])=[C:6]([O:42][CH2:43][CH3:44])[CH:7]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1ccc(CC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(CC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a mixture of rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-ethoxy-benzoic acid ethyl ester (50.0 mg, 0.076 mmol) in THF/MeOH (1.2 mL/0.4 mL) was added 4 N LiOH (0.4 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-ethoxy-benzoic acid (24.4 mg, 50.9%). HRMS (ES+) m/z Calcd for C33H32Cl2F2N2O4+H [(M+H)+]: 629.1780, found: 629.1782.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 59.8 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-trifluoromethyl-benzyl bromide (145 mg, 0.6 mmol) to afford title product (135 mg, 60% yield); LCMS; 100% APCI+, Calcd: +451.49. Found m/z: 452.3 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 5.07 (s, 2H), 6.87 (s, 4H), 7.53 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cc(Cl)cc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,5-dichlorobenzoyl chloride: ESMS m/e: 490.0 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20])(O)=O.N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[CH2:1]=[C:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20]
Reactant: O=C(O)C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Agent: C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
(3R)-6-Carboxy-5-oxo-1-thia-4-azacyclotridecane -3-carboxylic acid (1.71 g, 5.64 mmol) is dissolved in pyridine (20 ml) and piperidine (0.096 g, 1.13 mmol) is added followed by paraformaldehyde (0.25 g, 8.46 mmol). The mixture is heated to 65° C. and stirred for 2 hours. The mixture is cooled to room temperature, poured into 6N hydrochloric acid (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts are washed with brine (1×100 ml), dried (MgSO4) and solvent is evaporated to give (3R)-6-methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid, m.p. 184°-186° C.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:3]([O:5][CH3:6])=[O:4].C(O[C:29]([CH3:32])([CH3:31])[CH3:30])(=O)C.Cl(O)(=O)(=O)=O>>[C:29]([O:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 64.8 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (142 mg, 0.435 mmol) in tert-butyl acetate (2.94 mL, 21.76 mmol) was treated with perchloric acid (0.075 mL, 0.870 mmol), and then kept in the refrigerator without stirring for 2 days. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (108 mg, 0.282 mmol, 64.9% yield) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.71 (br. s., 1H), 7.39-7.31 (m, 2H), 7.30-7.24 (m, 2H), 7.18 (t, 1H), 6.09 (t, J=2.5 Hz, 1H), 5.38 (s, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H), 0.94 (s, 9H); LCMS (m/z) ES+=383 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[C:22](=[O:24])=[O:23].[K+].[Br-]>C1COCC1>[C:22]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1)([OH:24])=[O:23]
Reactant: Brc1ccc2c(c1)COCC2
Reactant: O=C=O
Agent: [Br-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)COCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 7-bromoisochroman (7 g; 32.86 mmol) in THF (100 ml) was cooled to -78° C. and treated with 40.6 ml of a 1.7M solution of tert-butyllithium in pentane (69 mmol; 2.1 eq). Powdered dry ice (excess) was added to the red anion solution within 45 seconds. The reaction mixture was stirred for 30 minutes at -78° C. and 1 hour at room temperature. The reaction was quenched with 60 ml of 1N HCl and extracted with 3×70 ml of ether. The ether layers were combined and washed with brine until the pH was neutral, dried with MgSO4, and concentrated in vacuo. The product was obtained as a white solid, mp 140°-142° C. (5.7 g; 82%). 1H NMR (CDCl3): δ2.95 (t, 2H); 4.03 (t, 2H); 4.83 (s, 2H); 7.24 (t, 1H); 7.89 (s, 1H); 7.92 (d, 1H). IR (KBr): 2954, 2561, 1684, 1427, 1293, 1108 cm-1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCNCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(Cc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
Methanesulfonyl chloride (18.9 g, 0.1655 mol) was added dropwise at 0° C. to a solution of N-benzyl ethanolamine (10 g, 0.0662 mol, from step (i) above) and triethylamine (27.6 ml, 0.1987 mol) in dichloromethane (100 ml). The reaction mixture was stirred at RT for 3 h under nitrogen atmosphere and partitioned between water and dichloromethane. The organic layer was separated, washed with water and brine and dried over sodium sulfate. Thes solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane, as eluent to give the sub-title compound (12 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
3-Methyl-2-nitrophenol (11.4 g, 74.4 mmol) was dissolved in chloroform (11 ml) and cooled on an ice-water bath. Bromine (3.8 ml, 74.4 mmol) in HOAc (9 ml) was added drop wise to the stirred, cooled solution. The solution was stirred at 0° for 2 h. Ice was added to the reaction mixture. The organic phase was separated and the water phase was extracted with chloroform. The combined organic phase was washed with brine and water. Evaporation gave 17.2 g. MS (ESI+) for C7H6BrNO3 m/z 232, 234 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C@@H:8]([CH2:15][CH3:16])[N:7]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:6]=2[N:5]=1.[CH3:24]I>CC(N(C)C)=O>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH3:24])[C:9](=[O:14])[C@@H:8]([CH2:15][CH3:16])[N:7]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:6]=2[N:5]=1
Reactant: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
60% sodium hydride in mineral oil (22.41 mg, 0.56 mmol) was added to a mixture of (R)-2-chloro-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-7,8-dihydropteridin-6(5H)-one (169 mg, 0.53 mmol) and methyl iodide (36.54 μL, 0.59 mmol) in dimethylacetamide (1.7 mL). The reaction mixture was stirred at room temperature for 1 hour. Ice was added to the reaction mixture. A solid crashed out and was filtered off, rinsing with water. The solid was dried in a pistol under vacuo at 70° C. The compound was obtained as a white solid (165 mg, 94% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([C:27]1[C:31]([CH:32]2[CH2:35][C:34](=O)[CH2:33]2)=[CH:30][N:29]([C:37]2[C:42]([Cl:43])=[CH:41][C:40]([C:44]([F:47])([F:46])[F:45])=[CH:39][C:38]=2[Cl:48])[N:28]=1)#[N:26].O>C(Cl)Cl>[C:25]([C:27]1[C:31]([CH:32]2[CH2:35][C:34](=[C:20]([Br:24])[Br:21])[CH2:33]2)=[CH:30][N:29]([C:37]2[C:38]([Cl:48])=[CH:39][C:40]([C:44]([F:45])([F:46])[F:47])=[CH:41][C:42]=2[Cl:43])[N:28]=1)#[N:26]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=C(Br)Br)C1
Temperature: -10 °C
Yield: 81.9 %

Procedure:
Triphenylphosphine (560 mg, 2.14 mmol) was dissolved in 2 ml anhydrous DCM and cooled to -10° C. Carbon tetrabromide (355 mg, 1.07 mmol in 2 ml DCM) was added dropwise to the cooled solution, producing an amber colour. 3-Cyano-4-(3-oxocyclobutyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (200 mg, 0.53 mmol, Example 3) in DCM (2 ml) was added dropwise whereupon the reaction mixture assumed a brown colour. The reaction mixture was warmed to room temperature. After 0.5 hr the mixture was poured into water (20 ml) and extracted with DCM (3×20 ml). The combined organics were washed (brine), dried (Na2SO4), filtered and the solvent removed in vacuo to leave a brown solid. This was purified by silica chromatography (eluting with 50% DCM/hexane) to yield 230 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].Cl.[C:13]1([C@H:19]2[CH2:21][C@@H:20]2[N:22]2[C:30](=[O:31])[C@@H:25]3[CH2:26][NH:27][CH2:28][CH2:29][N:24]3[C:23]2=[O:32])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:27]1[CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]([C@H:20]3[CH2:21][C@@H:19]3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:30](=[O:31])[C@@H:25]2[CH2:26]1)=[O:11]
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1Cl)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
2,3-Dichlorophenyl isocyanate (1.1 eq.) was added to a stirred solution of D2 and DIPEA (3.0 eq.) in DCM (0.09 M) and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 10-80% EtOAc/petroleum ether to give the title compound in 67% yield, 92% de by SFC. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.80 (1H, s), 7.45-7.42 (2H, m), 7.34-7.28 (3H, m), 7.23-7.18 (3H, m), 4.35 (1H, dd, J=12.9, 4.2 Hz), 4.14-4.09 (2H, m), 3.92 (1H, dd, J=13.0, 2.7 Hz), 3.07-2.99 (2H, m), 2.91 (1H, td, J=12.6, 3.0 Hz), 2.68 (1H, m), 2.39 (1H, ddd, J=9.8, 6.8, 3.2 Hz), 1.51 (1H, ddd, J=9.5, 5.7, 4.3 Hz), 1.41 (1H, dd, J=14.0, 7.1 Hz). MS (ES+) C22H20Cl2N4O3 requires 458, 460, found: 459, 461 (M+H+).