Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>O1CCCC1.O>[Si:15]([O:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16]
Reactant: OCC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 1-phenylethane-1,2-diol (10 g, 72.38 mmol, 1.00 equiv), TBSCl (22 g, 145.97 mmol, 2.00 equiv) and triethylamine (14.7 g, 145.27 mmol, 2.00 equiv) in tetrahydrofuran (100 mL). The solution was stirred overnight at room temperature. The next day it was diluted with 150 mL of H2O and the mixture was extracted with 3×80 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). Purification afforded 17 g (93%) of 2-[(tert-butyldimethylsilyl)oxy]-1-phenylethan-1-ol as a white oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.CO.CCCCCC>CCOC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CNC(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CNC(C)C)c1C
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A suspension of 71 mg of N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-2'-[[(1-methylethyl)amino]methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (prepared as in Step (A) of Example 43) was heated to reflux in ~3 ml of EtOAc. MeOH was added dropwise until complete dissolution occurred. Hexane was added to the hot mixture to the point of slight turbidity. After cooling to room temperature and standing several hours, the crystals were filtered and dried to afford 39 mg (55%) of the title compound of this Example as a colorless crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CC[O:39][CH2:38][CH2:37]1.C(Cl)(=O)C>C(Cl)Cl>[C:38]([NH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1)(=[O:39])[CH3:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Reactant: CN1CCOCC1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared in Example 58, 110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Acetyl chloride (16 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded N-[1-(3-acetylamino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (68 mg, 57%) as a white powder: ESI-LRMS m/e calcd for C27H31ClN4O4S [M+] 542.18, found 543.17 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.23 (m, 2H, CH2), 1.41-2.00 (m, 8H, 4×CH2), 2.15 (s, 3H, NCH3), 2.16-2.27 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 5.09 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 6.87 (d, Jo=7.5 Hz, 1H, Ar), 7.21-7.28 (m, 2H, NH and Ar), 7.28-7.33 (m, 2H, Ar), 7.35-7.41 (m, 1H, Ar), 7.44 (dd, Jo=8.1, Jm=1.3 Hz. 1H, Ar), 7.58 (d, Jm=1.3 Hz, 1H, Ar), 7.90-8.20 (m, 2H, Ar and NH).
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[NH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O(C(C)(C)C)[K]>C1(C)C=CC=CC=1.C(OCC)C.O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)O[K]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 50 mg (0.09 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.70 g (4.14 mmol) of Ph2NH and 0.58 g (5.17 mmol) of KO-t-Bu in 2 mL of toluene. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-pyridyldiphenylamine. LC-MS Found: 247.3 (M++1).
Reaction SMILES: [C:1]([N:5]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])(=[O:4])[CH2:2][CH3:3].[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>[N+](C)([O-])=O>[N+:19]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:6][CH2:7][CH3:8])[CH2:18]2)([O-:21])=[O:20]
Reactant: CCCN(C(=O)CC)C1COc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: CCCN(C(=O)CC)C1COc2ccc([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To an ice cool solution of 730 mg (2.96 mmol) 3-(N-propionyl-N-n-propylamino)chroman (16) in nitromethane (15 ml) was a mixture of fuming nitric acid (0.70 ml) and concentrated sulphuric acid (1.42 ml) added. The solution was stirred for 90 min at 0° C. The reaction mixture was poured out on ice and the product was extracted with dichloromethane. The organic layer was washed with water and 5% aqueous Na2CO3. The organic layer was separated, dried (MGSO4) and the solvent was evaporated yielding 700 mg (81%) of 6-nitro-3-(N-propionyl-N-n-propylamino)chroman (17).
Reaction SMILES: [NH2:1]C1C=NC2C(C=1NCCCCC(OCC)=O)=CC=CC=2.C(OCC(Cl)=O)C.[CH2:29]([O:31][CH2:32][C:33]1[N:34]([CH2:46][CH2:47][CH2:48][CH2:49][C:50](OCC)=[O:51])[C:35]2[C:44]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N:38]=[CH:37][C:36]=2[N:45]=1)[CH3:30].C([O-])(=O)C.[NH4+].[OH-].[Na+]>>[CH2:29]([O:31][CH2:32][C:33]1[N:34]([CH2:46][CH2:47][CH2:48][CH2:49][C:50]([NH2:1])=[O:51])[C:35]2[C:44]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N:38]=[CH:37][C:36]=2[N:45]=1)[CH3:30]
Reactant: CCOC(=O)CCCCNc1c(N)cnc2ccccc12
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCC(=O)OCC
Agent: CC(=O)[O-]
Agent: CCOCC(=O)Cl
Agent: [NH4+]
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Temperature: 110 °C

Procedure:
Ethyl 5-(3-aminoquinolin-4-ylamino)pentanoate, prepared in Parts A and B of Example 34, was treated as described in Part A of Example 36. Ethoxyacetyl chloride was used instead of methoxypropionyl chloride. Ethyl 5-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate (6.0 g, 17 mmol) and ammonium acetate (15 g) were sealed in a high-pressure vessel and heated for four days at 110° C. and then allowed to cool to ambient temperature. Aqueous sodium hydroxide (10%) was added, and the mixture was then extracted with dichloromethane (3×). The product crystallized from the dichloromethane and was collected in two crops to provide 2.64 g of 5-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanamide as an off-white solid, mp 157-158° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C@H:9]([C:11](=[O:41])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:43]([OH:54])(=O)[C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:32][C:28]1[CH:27]=[C:26]2[C:31](=[CH:30][CH:29]=1)[C:22]([CH2:21][N:18]1[C:17]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:16]=3[N:15]([C:48](=[O:50])[C:47]3[CH:46]=[CH:45][C:44]([C:43]([N:15]4[C:16]5[CH:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][C:17]=5[N:18]([CH2:21][C:22]5[C:31]6[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=6)[CH:25]=[CH:24][C:23]=5[O:33][CH3:34])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:41])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:42])[CH3:8])[CH3:10])[CH2:14]4)=[O:54])=[CH:52][CH:51]=3)[CH2:14][C@H:13]([NH:12][C:11](=[O:41])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:42])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[C:19]1=[O:20])=[C:23]([O:33][CH3:34])[CH:24]=[CH:25]2
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.5 %

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-7-cyano-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 4) (120 mg, 0.189 mmol) in pyridine (2 mL) was added terephthalic acid (20.604 mg, 0.113 mmol). After 10 min, the mixture was cooled to 0° C., POCl3 (0.036 mL, 0.396 mmol) was added and the cooling bath was removed. After 1 h, the mixture was concentrated, the residue was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to provide tert-butyl N-[(1S)-2-[[(3S)-1-[(6-bromo-2-methoxy-1-naphthyl)methyl]-5-[4-[(3S)-1-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-7-cyano-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzoyl]-7-cyano-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (6 mg, 1%) as an off white solid. LC-MS: 1403.2 (M+H).
Reaction SMILES: [Li]CCCC.C(=O)=O.CC(C)=O.Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1.[CH:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25].CC(O)=O>C1COCC1.[NH4+].[Cl-].CO>[Br:20][C:16]1[N:15]=[C:14]([CH:21]([OH:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][CH:17]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCCC=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCCCC(O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of nBuLi (26.40 mL of a 1.6M solution in hexanes, 42.24 mmol) in THF (25 mL) at −78° C. (dry-ice/acetone bath) was added a solution 2,6-dibromopyridine (10.00 g, 42.21 mmol) in THF (60 mL) drop-wise over 45 minutes under nitrogen. The resulting dark green coloured solution was stirred at −78° C. for 15 minutes and then valeraldehyde (6.70 mL, 63.01 mmol) was added drop-wise over 1 minute. The resulting dark purple coloured solution was stirred at −78° C. for 15 minutes and was then treated in one portion with a mixture of methanol (42 mL) and AcOH (2.70 mL, 47.16 mmol). The resulting pale yellow coloured solution was then allowed to warm to rt slowly over 1 hour. The mixture was then diluted with saturated aqueous NH4Cl (200 mL) and the product extracted with EtOAc (2×200 mL). The combined organic layer was then washed with brine (250 mL), dried (MgSO4), filtered and reduced to an orange oil (10.31 g, 100%). Purification of 7.14 g of this material by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 1:1) afforded the title compound as a clear, pale yellow oil (4.48 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[N:11]1([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]2[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=[N:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: NC(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncc(-c2ccc(F)cc2)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
1.2 g of Pd[P(Ph)3]4 and 7.6 g of p-fluorobenzeneboronic acid are added to a solution of 14.3 g of 5-bromonicotinic acid morpholinamide in 100 g of THF. A solution of 8.0 g of Na2CO3 in 25 g of water is subsequently added dropwise with stirring at 65° C. After 16 hours, the reaction mixture is cooled and evaporated in a rotary evaporator. The residue is taken up in dichloromethane, activated carbon is added, and the mixture is filtered. Repeated extraction of the filtrate with water and evaporation in a rotary evaporator gives a residue of 15.7 g, which, according to HPLC, comprises 89% of 5-(4-fluorophenyl)pyridine-3-carboxylic acid morpholinamide (net yield 93% of theory). Recrystallisation from ethyl acetate gives 8.0 g of 5-(4-fluorophenyl)pyridine-3-carboxylic acid morpholinamide having an HPLC purity of 99.6% (53.3% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3/[CH:16]=[CH:17]\Cl)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(/C=C\Cl)c2[C@@H]2CCCN12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
2.5 g (7.5 mmol) of (S)-8-chloro-1-[(Z)-2-chlorovinyl]-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was heated to boiling under reflux for 5 hours together with 1.66 ml (11.2 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 400 ml of water and the crystals obtained were filtered off. After drying and recrystallization from N,N-dimethylformamide there was obtained (S)-8-chloro-1-ethynyl-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 324°-325°.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CCN(C(C)C)C(C)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NS(=O)(=O)c2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
To 6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8.2 mg, 0.021 mmol) and DIEA (5.4 mg, 0.042 mmol) in dichloromethane (1.0 ml) was added benzenesulfonyl chloride (3.7 mg, 0.021 mmol) at RT for 2 hrs. The reaction mixture was quenched with pH 7 phosphate buffer (2 ml), dried over Na2SO4, concentrated and purified by silica gel flash chromatography to isolate 377 as a yellow film (3 mg, 29%). [M+H]+=496.1.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:7]=1[NH2:20]>C(O)(=O)C.C(Cl)Cl>[Cl:5][C:6]1[C:7]2[N:20]=[N:1][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Cc1ccccc1Nc1ncnc(Cl)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccccc1-n1nnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
Sodium nitrite (0.323 g, 4.69 mmol) was added to 6-chloro-N4-o-tolylpyrimidine-4,5-diamine (Intermediate AP5)(1 g, 4.26 mmol) in acetic acid (50% Aq) (25 mL)and DCM (25 mL) at room temperature. The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was separated and the organic phase was washed with water (10 mL), dried (MgSO4) and evaporated to give crude 7-chloro-3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (0.980 g, 94%) that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH3:15])=[O:5])[CH3:2].[CH3:16]I.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:16])[C:7]=1[CH3:15])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-water bath cooled solution of 2-methyl-1H-indole-3-carboxylic acid ethyl ester (5.197 g, prepared according to Suzuki et al. (1984) Synthesis (Stuttgart) 7:616-617), MeI (2.07 mL) in DMF (25 mL) was added NaH (1.33 g, 60% purity in mineral oil) under nitrogen gas stream. The reaction was stirred for 10 min at 0° C. and 20 min at room temperature and then quenched with diluted HCl solution, diluted with ice/water to a volume of ˜200 mL; the mixture was cooled with ice/water bath and the solids were collected with filtration, washed with water, and dried under high vacuum to give the desired crude product (5.87 g) as loose brown to yellow solid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.14-8.0 (m, 1H), 7.3-7.1 (m, 3H), 4.38 (q, 2H, J=7.1 Hz), 3.69 (s, 3H), 2.77 (s, 3H), 1.45 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:46]=[C:47]([CH2:51][C:52](O)=[O:53])[CH:48]=[CH:49][CH:50]=1.CCN(C(C)C)C(C)C>O.CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([CH2:51][C:52]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[S:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:53])[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-chlorophenylacetic acid (63.8 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{1-[(3-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (42.3 mg) as a yellow solid. LC/MS (ES) m/z=420.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (s, 2H) 3.93 (s, 2H) 4.26 (s, 2H) 5.41 (br. s., 2H) 7.20-7.30 (m, 3H) 7.32-7.36 (m, 2H) 7.37-7.40 (m, 2H) 7.42 (s, 1H) 7.82 (d, J=5.56 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1>CCO>[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([O:14][CH2:1][CH3:2])=[O:13])[CH2:7]1
Reactant: CC(=O)Cl
Reactant: C[C@H]1CCN[C@H](C(=O)O)C1
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@@H](C)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of dry EtOH (65 mL) and acetyl chloride (6.52 mL added dropwise at 0° C.) was added (2S, 4S)-4-methyl pipecolic acid (2.8 g, 19.6 mmol) at room temperature. The reaction was stirred at room temperature for 16 hrs and then concentrated in vacuo to give the title compound, (3.01 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.S1C=CC=C1[Li].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:25])[CH3:24]
Reactant: COc1cccs1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Li]c1cccs1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1ccc(OC)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Methoxythiophene (15.4 g) is dissolved in 100 ml anhydrous THF and butyl lithium (0.135 moles) in hexane is added dropwise. The solution is stirred at room temperature 15 hr and then heated at reflux for 1 hr. After cooling, the clear solution is tranferred to a dropping funnel by means of a siphon. The solution of thienyl lithium is added dropwise to a solution of diethyl oxalate (19.7 g) in 150 ml THF at -78° C. After stirring 2 hr at -78° C, the mixture is brought to -10° C and treated with saturated NH4Cl solution. The aqueous fraction is separated and extracted several times with ether. The combined ether extracts are washed with water and brine, dried (MgSO4) and concentrated. Chromatography on silica gel (eluant = benzene) gives 5-methoxy-2-thiopheneglyoxylic acid ethyl ester (2; X1 = CH3O, X2 and X3 = H and R10 = C2H5); mp 136° - 137° C after recrystallization from benzene-hexane.