Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[N:6]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:5]2=[O:27].[C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH2:41][CH2:42]O)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.CN(C=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH2:41][CH2:42][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[N:6]([CH2:20][C:21](=[O:22])[NH:23][CH:24]([CH3:25])[CH3:26])[C:5]2=[O:27])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: COc1cccc(-c2nc3ccc(O)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ccc(OCCC4CCCCN4C(=O)OC(C)(C)C)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of 2-[6-hydroxy-2-(3-methoxy-phenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropyl-acetamide (INTERMEDIATE IV.4) (200 mg, 0.55 mmol), N-Boc-2-piperidine ethanol (250 mg, 1.09 mmol) and resin-bound triphenylphosphine (˜3 mmol/g, 543 mg, 1.63 mmol) in dichloromethane (4.5 mL) and DMF (0.5 mL) was cooled to 0° C. and diisopropylazodicarboxylate (DIAD) (0.21 mL, 1.09 mmol) was added dropwise with stirring. The reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. The mixture was then filtered and concentrated in vacuo. The crude residue was dissolved in dichloromethane (100 mL) and washed with 1 N NaOH (aq.) and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel with ethyl acetate:hexane (2:1, v/v) afforded 2-{2-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]ethyl}piperidine-1-carboxylic acid tert-butyl ester (65 mg, 0.11 mmol, 20%).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3ccc(F)c(C)c3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-fluoro-3-methylphenylboronic acid to give the title compound as grey solid in 86% yield. MS: 299.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:49])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31](NCC(N[C@@H](C(O)=O)CCCCN)=O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].C[OH:53]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:49])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C@@H:14]3[C:25]3[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31]([OH:32])=[O:53])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-Benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 7) (0.010 g, 0.020 mmol) in methanol (2 ml) was added NaBH4 (0.010 g, 0.265 mmol). After 15 min the reaction was quenched by the addition of an aqueous solution of hydrochloric acid (1M, 1 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][CH:34]=1.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>C(Cl)Cl>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:34][CH:35]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Yield: 27.4 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.35 g, 0.75 mmol) was reacted with 1-(4-amino-phenyl)-ethanone (Aldrich) (0.12 g, 0.9 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.33 mL, 2.6 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (0.12 g, 27%).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:8]([F:30])=[C:9]([CH:14]([O:27][CH2:28][CH3:29])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[O:16])[C:10]([F:13])=[CH:11][CH:12]=1.C(Cl)(=O)C>>[C:1]([NH:5][CH2:6][C:7]1[C:8]([F:30])=[C:9]([CH:14]([O:27][CH2:28][CH3:29])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[O:16])[C:10]([F:13])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(CN)c1F
Solvent: CC(=O)Cl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(CNC(C)=O)c1F

Procedure:
In analogy to example 87.2 (RS)-2-(3-aminomethyl-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide acetic acid was reacted with acetyl chloride to give (RS)-2-[3-(acetylamino-methyl)-2,6-difluoro-phenyl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide. White foam. MS 402.5 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]3C(=O)C4=CC=CC=C4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][N:36]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=O.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[C:22]([CH2:23][NH2:24])=[N:21][N:20]=[C:19]3[CH2:35][N:36]=[C:7]([C:9]3[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=3[F:16])[C:6]=2[CH:17]=1
Reactant: O=C(c1cc(Cl)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 22, 5-chloro-2',6'-difluoro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-chloro-1-(aminomethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3cccs3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3cccs3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(thiophen-2-yl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:14](=O)[CH2:15][Cl:16])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([CH2:14][CH2:15][Cl:16])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2cc(C(=O)CCl)sc2C1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCc2cc(CCCl)sc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
A mixture of 2.1 g of 7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine in 5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirred at room temperature for 12 hours. The mixture was poured into water, made alkaline and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on a silica gel to give 1.8 g of 7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: OS(O)(=O)=O.N[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[CH2:15][CH3:16].N([O-])=[O:18].[Na+]>O>[CH2:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[OH:18])[C:11]#[N:12])[CH3:16]
Reactant: O=N[O-]
Reactant: CCc1cc(C#N)ccc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1cc(C#N)ccc1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Concentrated H2SO4 (3.4 mL) was added dropwise to a solution of 4-amino-3-ethylbenzonitrile (6.84 mmol) in H2O (12 mL) at 0° C. A solution of NaNO2 (7.52 mmol) in H2O (5 mL) was added dropwise at 0° C. to the resulting mixture. The reaction was stirred at 0° C. for 30 min and at 100° C. for 2 h. The mixture was cooled to room temperature and extracted with EtOAc. The organic layer was washed (H2O), dried and concentrated to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].IC.[C:14]([O-])(=O)C.[Na+]>C1COCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][CH3:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1cc(OC)cc(OC)c1
Yield: 29.9 %

Procedure:
A solution of 3,5-dimethoxyaniline (13.8 g, 90 mmol), Iodomethane (12.7 g, 90 mmol), and sodium acetate (7.4 g, 90 mmol) in 100 ml of anhydrous THF was stirred under nitrogen atmosphere for 10 hr. Then, THF was removed by rotary evaporation. The crude product was partitioned between water and ethyl ether. The ethereal extraction was separated and washed with water, brine, and dried over Na2SO4. Filtration and removal of solvent provided 13.6 g of crude product. The crude product was chromatographed on silica gel (33% acetone-petroleum ether) to afford the expected product 4.5 g (27% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16](OCCCC)=[O:17])[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[NH3:25]>CO.O1CCCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([NH2:25])=[O:17])[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)sc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl (5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 2, 685 mg, 1.95 mmol) is treated with 7N ammonia in MeOH (19 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) and tetrahydrofuran (20 mL) and stirred at ambient temperature for 1 h. The resulting slurry is concentrated under reduced pressure and then triturated and filtered from acetone to give the title compound, mp 274-276° C. (dec.); MS (ESI−) for C12H11N3O4S m/z 292 (M−H)−; [α]25D−27 (c 0.98, DMSO).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12](O)=[O:13]>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:12]=[O:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccc(O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
4-Amino-3-nitrophenol (36 g, 234 mmol) was split into 3 batches, approximately 12 g each. Each batch was dissolved in 150 mL of tetrahydrofuran and heated with 10 mL of 96% formic acid at 95 degrees Centigrade for 4 hours. The 3 batches were combined and concentrated. As the reactions had only proceeded ˜10% to completion, the reaction mixture was dissolved in 100 mL of 96% formic acid and heated at 110 degrees Centigrade. After 30 minutes, a precipitate began to form and 150 mL of tetrahydrofuran was added to ensure good stirring. The reaction was heated at 110 degrees Centigrade for 15 hours. The reaction was concentrated and the residue was diluted with water. The resulting solid was collected by filtration. The solid was washed three times with water and then dried in a vacuum oven at 110 degrees Centigrade for approximately 18 hours to give 40.4 g of (4-hydroxy-2-nitrophenyl)formamide. (M-1) 181.0, 1.48 min (LC/MS method B)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[OH-].[Na+].CC(C)=O.O>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
7.6 g 4-Aminophenylacetic acid are dissolved in 50 ml 2 N aqueous sodium hydroxide solution and 50 ml acetone. A solution of 8.8 g 4-chlorobenzoyl chloride in 10 ml acetone is added dropwise thereto at 0° C. The reaction mixture is further stirred for 3 hours at ambient temperature, then diluted with water, filtered and the filtrate acidified with dilute hydrochloric acid. The precipitate obtained is reprecipitated via its sodium salt and recrystallized from ethanol. There are obtained 4.2 g (29% of theory) 4-(4-chlorobenzamido)-phenylacetic acid; m.p. 252° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.Cl>C(Cl)Cl>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Aminophenyl-acetylene (1.17 g, 10 mmol) was added to DCM (30 mL), and Et3N (2.8 mL, 20 mmol) was added thereto. (BOC)2O (2.3 g, 10 mmol) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, 1N HCl was added, which was then extracted with EtOAc and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[C:19]([Zn]C#N)#[N:20].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:19]([C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1)#[N:20]
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a 10 ml microwave vial was added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (500 mg, 1.612 mmol), dicyanozinc (150 mg, 1.277 mmol) and DMF (5 mL). The mixture was degassed and stirred at rt under N2 for 15 min. To the mixture was added palladium tetrakis (118 mg, 0.102 mmol) and the reaction was stirred at 95° C. for 1 h. The reaction was allowed to cool and poured into saturated aqueous Na2CO3 (50 mL) and EtOAc (50 mL) and stirred for 20 min. The mixture was extracted with ether (100 ml) and EtOAc (100 ml) (1:1), followed by filtration and evaporation to yield a residue. The residue was purified by silica gel chromatography (Analogix IF280, 0-8% EtOAc/hexanes, SF25-40 g, 30 minutes) to give methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (130 mg, 0.497 mmol, 38.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J=1.52 Hz, 1H) 7.82 (s, 1H) 7.71 (d, J=1.52 Hz, 1H) 4.85-4.97 (m, 1H) 3.90 (s, 3H) 2.29 (s, 3H) 1.45 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 257.4.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][CH2:30][CH2:31][OH:32])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(O)(C(F)(F)F)=O.CO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([CH2:29][CH2:30][CH2:31][OH:32])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CCCO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2ncc(CCCO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxypropyl)pyrimidin-2-yl)thiophene-2-sulfonamide (10 mg, 0.02 mmol) in TFA (1 mL) was heated to reflux for 0.5 h. The reaction was removed in vacuo, to which K2CO3 (43 mg, 0.31 mmol) in MeOH (5 mL) was added. After stirring at room temperature for 1 h the reaction mixture was filtered, the filtrate was concentrated and purified by HPLC-prepare to afford the desired compound 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxy propyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 311) (6 mg, 66.7%, two step). LC-MS (m/z)=421 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 0.75-0.79 (m, 2H), 0.99-1.03 (m, 2H), 1.71 (q, J=6.4 Hz, 2H), 1.94-1.99 (m, 1H), 2.71 (t, J=6.4 Hz, 2H), 3.47 (t, J=6.4 Hz, 2H), 6.45 (s, 1H), 7.64 (d, J=4.0 Hz, 1H), 7.80 (s, 2H), 8.05 (d, J=3.2 Hz, 1H), 8.22 (s, 1H), 10.06 (bs, 1H).
Reaction SMILES: Cl.[C:2](=[NH:9])([NH2:8])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[O-]CC.[Na+].C(O[CH:17]=[CH:18][C:19](=O)[C:20]([F:23])([F:22])[F:21])C>C(O)C>[CH2:3]([C:2]1[N:8]=[C:19]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:17][N:9]=1)[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: C=CCCCC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCCCc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-hexenimidamide hydrochloride (P4, 200 mg) in ethanol (1.8 mL), sodium ethoxide (92 mg) was added and the mixture stirred at r.t. for 5 min. 4-(Ethyloxy)-1,1,1-trifluoro-3-buten-2-one (0.13 mL) was then added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated, the residue was dissolved in dichloromethane and the organic layer was washed with H2O and dried over Na2SO4. This solution was filtered and the filtrate was concentrated in vacuo. The crude was purified by column chromatography (eluting with dichloromethane/methanol 95/5) to give 143 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH2:22][CH2:23]Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:23][CH2:22][O:21][CH3:20])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COCCCl
Reactant: COC(=O)c1cc(O)cc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 140 °C
Yield: 93.8 %

Procedure:
A mixture of methyl 3-cyano-5-hydroxybenzoate (302 mg, 1.7 mmol), potassium carbonate (471 mg, 3.4 mmol) and 2-chloroethyl methyl ether (309 μL mg, 3.4 mmol) in N,N-dimethylformamide (4 mL) was heated in a sealed vial at 140° C. for 15 minutes. The reaction was cooled, diluted with ethyl acetate, washed with water and saturated brine, filtered and concentrated. Filtration through silica gel using dichloromethane afforded 375 mg (93%) of methyl 3-cyano-5-(2-methoxyethoxy)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:30]#[N:31])([CH2:24]OS(C)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:30]#[N:31])([CH2:24][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
After dissolving 230 mg of 2-methylphenol in 20 ml of N,N-dimethylformamide, 43 mg of sodium hydride (70% suspension in oil) was added and the mixture was stirred at 80° C. for 30 minutes. Next, 224 mg of 1-(tert-butoxycarbonyl)-4-cyano-4-(methanesulfonyloxymethyl)piperidine was added and the mixture was stirred at 100° C. for 8 hours. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The organic layer was washed with a 1N sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (273 mg, 100% yield).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.[H-].[Na+].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1>O>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([O:12][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=2)=[N:19][CH:20]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(COc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 4-fluorobenzyl alcohol (2.60 g, 20.6 mmol) was added sodium hydride (0.88 g, 22.2 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 10 minutes at room temperature. Next, 2,5-dibromopyridine (3.50 g, 14.8 mmol) was added at 0° C., and stirred for 19 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (3.75 g, 89.8%).