Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=O)C.[NH4+].[OH-]>O1CCCC1>[SH:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: CC(=O)SCC1(C(=O)NCC(O)C(=O)OCc2ccccc2)CCc2ccccc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(O)CNC(=O)C1(CS)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester (882 mg, 2.00 mmol) in tetrahydrofuran (20 mL) then add NH4OH (1 mL). Stir at ambient temperature under an atmosphere of argon for 24 hours, then concentrate in vacuo. Purify the residue by column chromatography (ethyl acetate:hexane) to give the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH:27]=[C:28]([C:34](OCC)=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]2[C:10]([N+]([O-])=O)=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH3:26])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)(=O)C>[CH:1]1([N:4]2[C:5]3[C:10](=[CH:9][C:8]([F:14])=[C:7]([N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]4)[C:6]=3[CH3:26])[C:34](=[O:35])[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=CN(c1c([N+](=O)[O-])cc(F)c(N2CCN(C(=O)OCC)CC2)c1C)C1CC1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a solution of diethyl [N-cyclopropyl-N-[3-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene]malonate (1.0 g) in acetic anhydride (5 ml) is added conc. sulfuric acid (2 ml) with keeping at 50°-70° C. After stirring for 30 minutes, the reaction mixture is poured into ice water, and neutralized with potassium carbonate. The mixture is extracted with ethyl acetate, and the solvent is distilled off, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:methanol=10:1) and then recrystallized from ethyl acetate to give ethyl 1-cyclopropyl-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.19 g), as colorless prisms, m.p. 200°-202° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:17]=3)=[CH:13][C:7]=2[C:6]=1[CH3:34])=[O:4].O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:34][C:6]1[C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:17]=3)[CH:11]=[CH:10][C:8]=2[S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc12
Reaction time: 16 h

Procedure:
To a stirred solution of methyl-3-methyl-5-[3-(2quinolinylmethyloxy)benzyloxy]benzo(b)thiophene-2-carboxylate (355 mg, 0.76 mmol) in THF (10 ml), methanol (10 ml) and water (10 ml) at room temperature is added lithium hydroxide monohydrate (156 mg, 3.71 mmol). The resulting solution is stirred for 16 hours and concentrated. The residue is suspended in water and washed with ether. The aqueous layer is acidified to pH 3. The precipitated solid is filtered, washed with water and methylene chloride and dried to provide 3-methyl 5-[3(2-quinolinylmethyloxy)-benzyloxy]benzo(b)thiophene -2-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:16]=2[CH:44]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[N:17]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[C:32]([C:37]([OH:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)[C:16]=2[CH:44]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc2ccc(NC(=O)NCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)NCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-benzylaminocarbonylamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH2:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])C.[ClH:29]>>[ClH:29].[NH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:17])[CH:12]=2)[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccccc12
Agent: Cl
Product: NCc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
3-Aminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 3-aminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid hydro-chloride as an off-white solid. MS: 347.4 ([M−H]−).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:45])[CH3:44]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:45][CH2:43][CH3:44])=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Product: CCNC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and ethylamine.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].C[O-].[Na+]>CO>[C:1]([C@@H:5]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](Cc2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](Cc2ccccc2)C[C@@H]2CC[C@H]1N2C

Procedure:
To a solution of (1R,2S,3S)-2-carbomethoxy-3-benzyltropane (5.6 g, 20.5 mmol) in absolute methanol (100 ml) was added a solution of sodium methanolate in methanol (2M, 2 ml) and the mixture was refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in diethyl ether and was washed with water. The organic phase was dried and concentrated in vacuo. The crude product was purified by column chromatography using a mixture of diethyl ether and pentane (1+1)+1% triethyl amine as eluent yielding (1R,2R,3S)-2-carbomethoxy-3-benzyltropane as oil. By dissolution of this product in diethyl ether and subsequent addition of a solution of hydrochloric acid in diethyl ether the title compound precipitated as white crystals, m.p. 188°-190° C.
Reaction SMILES: CS(C)=[O:3].C([O-])([O-])=O.[K+].[K+].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:27][CH:28]=3)[CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)#[N:12].OO>CO.O>[N:36]1([CH2:35][CH2:34][CH2:33][O:32][C:26]2[CH:25]=[C:24]3[C:29]([CH2:30][CH2:31][N:22]([S:19]([C:16]4[CH:17]=[CH:18][C:13]([C:11]([NH2:12])=[O:3])=[CH:14][CH:15]=4)(=[O:20])=[O:21])[CH2:23]3)=[CH:28][CH:27]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CS(C)=O
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1
Yield: 26 %

Procedure:
A 1.4 mL DMSO mixture of K2CO3 is stirred under N2, 2-(4-cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline (75 mg, 0.17 mmol) is added, 0.2 mL H2O added, followed by 30% H2O2 (1.4 mL, 12 mmol) and reaction is stirred at room temperature for 4 hours. The reaction mixture is diluted with MeOH, filtered, and the solids washed twice with MeOH. The filtrate is concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give the product as an off-white solid (26 mg, 26% yld). MS (ES+)458.2(M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[C:12]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:21][C:13]2[CH:12]=[CH:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=2)[CH:3]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(Cc2ccc(C(=O)O)cc2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl pyrazole-4-carboxylate (500 mg, 3.57 mmol) and bromo-para-toluic acid (767 mg, 3.57 mmol) in acetone (10 ml) was added potassium carbonate (2.465 g, 17.84 mmol). The suspension was stirred at 50° C. overnight. Water was added to the reaction, and the aqueous phase was washed with ethyl acetate. The pH of the aqueous phase was acidified with 1M hydrochloric acid, and the product was extracted with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (method G) Rt=1.642 min; UPLC (method F) Rt=0.69 min, [M+H]+275.3 [M−H]− 273.3.
Reaction SMILES: BrC1C=CC(Br)=CN=1.[F:9][C:10]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:14]2.[CH2:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].B1C2CCCC1CCC2>>[F:9][C:10]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:21][N:20]=2)[CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:14]2
Reactant: CCCCCCCCC1Cc2cc(-c3ccc(Br)cn3)cc(F)c2C1
Reactant: C=CCCCCCC
Agent: B1C2CCCC1CCC2
Agent: Brc1ccc(Br)nc1
Product: CCCCCCCCc1ccc(-c2cc(F)c3c(c2)CC(CCCCCCCC)C3)nc1

Procedure:
Obtained by reacting with 2,5-dibromopyridine to form 4-fluoro-6-(5-bromo-pyridine-2-yl)-2-octyl indane and subsequent reaction with the octene-9-BBN-adduct.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:3]=1.[BH:11]([OH:13])[OH:12].O1BOBOB1>>[CH:8]1([C:4]2[N:3]=[C:2]([B:11]([OH:13])[OH:12])[CH:7]=[CH:6][N:5]=2)[CH2:10][CH2:9]1
Reactant: Brc1ccnc(C2CC2)n1
Reactant: OBO
Agent: B1OBOBO1
Product: OB(O)c1ccnc(C2CC2)n1
Yield: 90 %

Procedure:
The title compound was prepared from 4-bromo-2-cyclopropylpyrimidine (WO 00/066566) in 90% yield (25 mmol scale) following the procedure by Li et al. (J. Org. Chem. 2002, 67, 5394-5397). LC-MS suggested that the product was composed of the boronic acid and the trimeric anhydride (sym-boroxine).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]12[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH2:26]>>[CH:19]12[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH:26][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: NC1CC2CCC1O2
Product: C(#Cc1cnc(NC2CC3CCC2O3)nc1)c1ccccc1

Procedure:
The title compound, MS: m/e=292.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and rac-(7-oxa-bicyclo[2.2.1]hept-2-yl)amine (can be prepared in accordance with the literature described in the patent EP 1958666).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:15]2[C:6]([C:7]3[CH:8]=[C:9]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:10]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[N:11][C:12]=3[CH:13]=[CH:14]2)=[N:5][N:4]=1.[NH4+:30].[OH-].II>C1COCC1>[OH:1][CH2:2][C:3]1[N:15]2[C:6]([C:7]3[CH:8]=[C:9]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:10]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:30])=[CH:22][CH:23]=4)=[N:11][C:12]=3[CH:13]=[CH:14]2)=[N:5][N:4]=1
Reactant: [NH4+]
Reactant: O=Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 14-2 (0.4 g, 1.1 mMol) in anhydrous THF (15 mL) was added 3 mL of concentrated NH4OH. The solution was then treated with iodine (0.4 g, 1.6 mMol) followed by stirring at room temperature overnight. The reaction was quenched with saturated sodium thiosulfate solution (20 mL) and the product was extracted into ethyl acetate three times. The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to yield 15-1 as a tan solid. Mass (M+1) calculated: 378.135 observed: 378.1345
Reaction SMILES: [C:1]([Si:3]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5])#[CH:2].[Li]CCCC.[CH3:18][N:19]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]1>O1CCCC1.CCOC(C)=O>[CH3:18][N:19]1[CH2:23][CH2:22][C:21]([C:2]#[C:1][Si:3]([CH:7]([CH3:9])[CH3:8])([CH:4]([CH3:6])[CH3:5])[CH:10]([CH3:12])[CH3:11])([OH:24])[CH2:20]1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: CN1CCC(=O)C1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](C#CC1(O)CCN(C)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure B. Into a solution of Ethynyl-triisopropyl-silane (1.1 g, 6 mmol) in tetrahydrofuran (10 mL) was dropped in n-BuLi (2.4 mL, 6 mmol) at −78° C. The solution was stirred for 0.5 h. Then 1-Methyl-pyrrolidin-3-one (0.5 g, 5 mmol) was added. The solution was allowed to warm up to room temperature and stirred for 3 h. Then the reaction mixture was added in 50 mL EtOAc and washed with water three times. The solvent was removed under vacuum to afford 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (0.55 g, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 5.53 (s, 1H), 2.74-2.63 (m, 2H), 2.46-2.44 (m, 1H), 2.23 (s, 3H), 2.13-1.96 (m, 2H), 1.07-0.97 (m, 21H). A solution of 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (1.0 g, 3.6 mmol) in tetrahydrofuran (10 mL) was treated with Tetrabutyl-ammonium fluoride (0.94 g, 3.6 mmol). The solution was stirred overnight at room temperature. Then the reaction mixture was purified by column (eluent: CH2Cl2: MeOH=10:1) to afford 3-Ethynyl-1-methyl-pyrrolidin-3-ol (0.26 g, 58%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 1H), 3.31 (s, 1H), 2.74-2.56 (m, 3H), 2.49-2.46 (m, 1H), 2.22 (s, 3H), 2.11-1.91 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].C(NC(C)C)(C)C.CN(C)C=O.[Br:18][C:19]1[CH:35]=[CH:34][C:22]2[C:23]3[N:24]=[C:25]([C:31](Cl)=[O:32])[S:26][C:27]=3[CH2:28][CH2:29][O:30][C:21]=2[CH:20]=1>C(OCC)(=O)C>[CH:3]([N:2]([CH3:1])[C:31]([C:25]1[S:26][C:27]2[CH2:28][CH2:29][O:30][C:21]3[CH:20]=[C:19]([Br:18])[CH:35]=[CH:34][C:22]=3[C:23]=2[N:24]=1)=[O:32])([CH3:5])[CH3:4]
Reactant: O=C(Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CNC(C)C
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(C)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-methylpropan-2-amine (0.265 g, 3.63 mmol) in N,N-Diisopropylamine (0.758 mL, 4.35 mmol) and N,N-Dimethylformamide (4.49 mL, 58.0 mmol) at room temperature was added 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl chloride (0.500 g, 1.45 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, washed with brine, and concentrated in vacuo to give 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid isopropyl-methyl-amide which was not further purified.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=[N:15]O)=[CH:4][CH:3]=1.Cl.CCO>CO.[Zn]>[NH2:15][CH2:14][C:5]1[C:6]([F:13])=[C:7]([C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)ccc(C=NO)c1F
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1c(Cl)ccc(CN)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was added nBuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at −78° C. and the reaction mixture was warmed to 0° C. over a period of 1 h. Then the reaction mixture was cooled to −78° C. and a solution of ethyl 2-chloro-6-fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at −78° C. for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h and then gradually warmed to 0° C. over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-formylbenzoate. 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.05-8.00 (t, J=7.8 Hz, 1H), 7.72-7.69 (d, J=8.4 Hz, 1H), 4.53-4.46 (q, J=6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J=6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq, solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55° C. for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. 1H NMR (300 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, J=8.1 Hz, 1H), 7.49-7.46 (d, J=8.4 Hz, 1H), 4.44-4.37 (q, J=7.5, 14.1 Hz, 2H), 1.34-1.29 (t, J=7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HCl in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3 h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of NaHCO3. The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. 1H NMR (300 MHz, CDCl3): δ 7.54 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 4.45 (q, J=7.5, 14.1 Hz, 2H), 4.11 (d, J=3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([P:7]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[C:24]([C:26]2[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][C:34]=4[CH2:36][P:37]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=O)[CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:22]=[CH:21]3)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C[SiH](Cl)Cl>C1(C)C(C)=CC=CC=1>[C:45]1([P:37]([CH2:36][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:35]=2[C:26]([C:24]2[C:25]4[C:20](=[CH:19][CH:18]=[CH:17][C:16]=4[CH2:15][P:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:21]=[CH:22][CH:23]=2)=[CH:27][CH:28]=[CH:29]3)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=P(Cc1cccc2cccc(-c3cccc4cccc(CP(=O)(c5ccccc5)c5ccccc5)c34)c12)(c1ccccc1)c1ccccc1
Agent: C[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: c1ccc(P(Cc2cccc3cccc(-c4cccc5cccc(CP(c6ccccc6)c6ccccc6)c45)c23)c2ccccc2)cc1

Procedure:
20.48 g (0.03 mol) of 8,8'-bis(diphenylphosphinylmethyl)-1,1'-binaphthyl are suspended in 75 ml of xylene and 36 ml (0.15 mol) of tri-n-butylamine in the absence of air and moisture, and 16.57 g (0.144 mol) of methyldichlorosilane are added dropwise with stirring. The mixture is then refluxed for 14 hours to give a clear solution. Xylene is distilled off at atmospheric pressure, and the mixture is allowed to cool with stirring. This results in the formation of 8,8'-bis(diphenylphosphinomethyl)-1,1'-binaphthyl as a colorless solid, which is filtered off under an inert gas and washed with 20 ml of degassed acetone. 16.7 g (87%) of colorless crystals of melting point 168° to 170° C. are obtained.
Reaction SMILES: [CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([O:29]C)=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([OH:29])=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)O
Temperature: 65 °C
Reaction time: 18 h
Yield: 125.8 %

Procedure:
To a stirred solution of methyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylthiazole-5-carboxylate (example 71A, 103 mg, 0.203 mmol) in MeOH (2 mL) was added NaOH (1.420 mL, 1.420 mmol). The solution was then stirred at 65° C. for 18 hrs. The reaction mixture was then cooled to room temperature and concentrated in vacuo to afford yellow slurry. The mixture was then diluted with water, brought to pH 4 with 1N HCl, and the precipitate collected by vacuum filtration. The filtrate was then extracted with CH2Cl2; the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude residue was then purified by silica-gel flash chromatography using an Isco 40 g column eluting from 0-8% MeOH/CH2Cl2. Desired fractions were combined with the collected precipitate and concentrated to afford 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylthiazole-5-carboxylic acid (126 mg, 126% yield) as an orange/yellow solid.