Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[C:39]2[C:34](=[N:35][CH:36]=[N:37][C:38]=2[Cl:40])[N:33]([CH3:41])[N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH2:30][C:31]2[C:39]3[C:34](=[N:35][CH:36]=[N:37][C:38]=3[Cl:40])[N:33]([CH3:41])[N:32]=2)[CH:9]=1)=[O:6]
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)c2ccc(NCCO)c(Cl)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2ccc(NCCO)c(Cl)c2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-(2-hydroxyethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide (34.2 mg, 0.11 mmol) and potassium carbonate (17.3 mg, 0.123 mmol) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (25.4 mg, 0.097 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step (described in Example 9) or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-chloro-N-[3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-4-methyl-phenyl]-4-(2-hydroxy-ethylamino)-benzamide as a white solid. (Yield 22 mg).
Reaction SMILES: [CH:1]([Cl:4])([Cl:3])[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[OH-].[K+]>CN(C=O)C.CO>[Cl:2][C:1]([Cl:4])([Cl:3])[CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH3:5])[CH:8]=1)[OH:11]
Reactant: COc1cccc(C=O)c1
Reactant: ClC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1.8 mL (22.5 mmol) of chloroform in 10 mL DMF was added 1.4 g (10 mmol) of 3-methoxybenzaldehyde. The reaction mixture was chilled to 0° C. and a solution of 0.40 g (7 mmol) of potassium hydroxide in 1.8 mL of methanol was added. The reaction mixture was stirred for 3 h at 0° C., then quenched by addition of 1 mL of 1 N hydrochloric acid. The reaction mixture was adjusted to pH=7, then extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH:15](C)[C:16]2(C)O[SiH3])[C:11](=[O:46])[O:10][CH:9]([C:47]([CH3:61])=[CH:48][CH:49]2[CH2:54][CH2:53][CH:52]([NH:55][C:56](=[O:58])[CH3:57])[CH:51]([O:59][CH3:60])[CH2:50]2)[CH:8]([CH3:62])[CH:7](C(C)(C)C)[CH2:6][C:5]1=[O:67])[CH:2]=[CH2:3].F.C(OCC)(=[O:71])C>C(#N)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:46])[O:10][CH:9]([C:47]([CH3:61])=[CH:48][CH:49]2[CH2:54][CH2:53][CH:52]([NH:55][C:56](=[O:58])[CH3:57])[CH:51]([O:59][CH3:60])[CH2:50]2)[CH:8]([CH3:62])[CH:7]([OH:71])[CH2:6][C:5]1=[O:67])[CH:2]=[CH2:3]
Reactant: CCOC(C)=O
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3C(CCC(C)C3(C)O[SiH3])C(=O)OC(C(C)=CC3CCC(NC(C)=O)C(OC)C3)C(C)C(C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: CC#N
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(C)=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A portion of the product from step (a) (13 mg) was dissolved in acetonitrile (4 ml) and to this was added 40% aqueous hydrofluoric acid (0.1 ml). After stirring for 2 hours at room temperature the reaction mixture was poured into ethyl acetate and the separated organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution and brine before being dried (MgSO4), filtered and evaporated to an oil in vacuo. Column chromatography on silica eluting with hexane/acetone [2:1] then gave the title compound (8 mg) as a foam.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[CH2:42][CH2:43][NH2:44]>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH2:42][CH2:43][NH:44][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([CH3:34])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: COc1ccc(CCNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc1OC

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3,4-dimethoxyphenethylamine, m.p. 130-136° C. MS [(+)ESI, m/z]: 600 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][N:19]([CH3:23])[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)N(C)C)cc23)CC1
Yield: 78.5 %

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.4 mg (0.059 mMol) dimethyl carbamoyl chloride, 13.2 mg (79%) of the title compound were recovered.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:29])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH:24]([CH2:27][F:28])[CH2:25][F:26])[CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1>C(Cl)Cl>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:29])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH:24]([CH2:25][F:26])[CH2:27][F:28])[CH:22]=3)[C:17]([NH:36][C:37]3[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(OC(CF)CF)c1
Reactant: Cc1cnc(N)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(CF)CF)c2)cn1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 57.9 %

Procedure:
1-Chloro-N,N-2-trimethylpropenylamine (0.08 mL, 0.60 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoic acid (215 mg, 0.5 mmol) in DCM (5 mL) and the reaction stirred at RT for 30-40 minutes. Pyridine (0.08 mL, 1.0 mmol) and 2-amino-5-methylpyrazine (108 mg, 1.0 mmol) were added and the reaction stirred for 16 hours before being concentrated in vacuo and water (20 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloric acid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the desired compound as a white solid (150 mg). 1H NMR δ (CDCl3): 2.40 (quintet, 2H), 2.56 (s, 3H), 4.22-4.31 (m, 2H), 4.32-4.40 (m, 2H), 4.62-4.82 (m, 5H), 7.06 (t, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 8.15 (s, 1H), 8.17 (s, 1H), 8.25 (d, 1H), 8.46 (s, 1H), 9.55 (s, 1H); m/z 518 (M+H)+, 516 (M−H)−
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IN1C(=O)C[CH2:27][C:26]1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:26]#[CH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 65 °C
Yield: 118.3 %

Procedure:
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) in anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) was heated at 65° C. under nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) using ethyl acetate/hexane (1:1 v:v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2SO3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.73 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.29 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0210 (M+H calculated for C19H16NO2FI requires 436.0196). Step 2. Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCO
Product: OCCC#Cc1cccc(CF)n1
Yield: 80.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(A), from 2-bromo-6-(fluoromethyl)pyridine (compound 190(E), 3.50 g, 18 mmol) and 3-butyn-1-ol (1.3 g, 18 mmol). The crude residue was purified over silicagel chromatography (prepacked 85 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 2.60 g of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-ol as an orange solid (Yield: 79%).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]=[S:22]>>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]1[S:22][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1
Reactant: NC1(CCl)CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([F:23])[CH:18]=3)[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:23][C:19]1[CH:18]=[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccnc(F)c3)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3ccnc(F)c3)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 9k using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.ClC(Cl)(Cl)C(=N)O[C:23]([CH3:26])([CH3:25])[CH3:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cccc(Cc2cc(Cl)ccc2O)n1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(Cl)cc1Cc1cccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 44 h
Yield: 24 %

Procedure:
To a solution/suspension of 6-[(5-chloro-2-hydroxyphenyl)methyl]-2-pyridine-carboxylic acid (308 mg) in dry dichloromethane (12 ml) was added t-butyl 2,2,2-trichloroacetimidate (1.67 ml) and boron trifluoride-diethyl etherate (0.05 ml) and the mixture stirred under argon at ambient temperature for 44 hours. Dichloromethane (15 ml) was added and the mixture washed with saturated sodium bicarbonate solution (15 ml). The aqueous layer was extracted with dichloromethane (2×15 ml) and the combined organic extracts washed with brine (25 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (91 mg, 24%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>>[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH2:14][CH:13]([C:3]2[CH:4]=[CH:9][CH:10]=[CH:11][CH:2]=2)[O:1][C:2]2[C:3]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[N:26]=1
Reactant: O=C1CCCc2c1ccc(O)c2CCc1ccccc1
Reactant: Cc1ncc[nH]1
Product: Cc1nc(CC(Oc2ccc3c(c2CCc2ccccc2)CCCC3=O)c2ccccc2)c[nH]1

Procedure:
The title compound was prepared using the procedure of Example 20, step 4 using 6-hydroxy-5-(2-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-one and 2-methylimidazole.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:26]=[O:27])=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][OH:27])=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2CO)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2′-formyl-biphenyl-4-carboxylic acid quinolin-7-ylamide, Example 28, (90 mg, 0.25 mmol) in MeOH (2 mL) was added sodium borohydride (20 mg, 0.51 mmol) and the mixture was stirred for 10 min at 0° C. The reaction mixture was diluted with EtOAc (50 mL) and washed with satd NH4Cl (5 mL). The EtOAc layer was separated, washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (gradient, 40 to 90% EtOAc/hexane) to provide the title compound as a yellow amorphous solid. MS (ESI, pos. ion.) m/z: 355 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CO[C@@H](C)C(=O)O
Agent: Cl
Product: CO[C@@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (63 mg, 61%), MS (ISP) m/z=417.4 [(M+H)+], mp 158.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (S)-2-methoxy-propanoic acid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Br:7][C:8]1[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[C:10](I)[CH:9]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[Br:7][C:8]1[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[C:10]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc(F)c(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (44 mL) followed by trimethylsilylacetylene (0.737 mL, 5.32 mmol) were added dropwise to a suspension of 4-bromo-5-fluoro-2-iodoaniline (1.4 g, 4.43 mmol), Pd(PPh3)2Cl2 (0.156 g, 0.222 mmol), and CuI (0.042 g, 0.222 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred for 2 h. The reaction was concentrated, diluted with Et2O, and filtered through Celite. The filtrate was washed with brine, dried (Na2SO4), filtered and concentrated. Chromatography over silica eluting with 2-8% EtOAc/hexanes afforded the desired product as a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][N:33]2C(OC(C)(C)C)=O>>[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][N:33]2[CH2:29][C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=3[CH3:13])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:31])[CH:15]=2)[C:20](=[O:24])[N:19]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[CH:18]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3C[C@@H]4C[C@H]3CN4)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid, tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: COc1ccccc1CN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: COc1ccccc1CNc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
2-Chloro-6-nitro-quinoline (0.80 g, 4.0 mmol) and 2-methoxybenzylamine (1.5 mL, 12 mmol) were heated at 130° C. for 2 h. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate, 9:1, 4:1, 1:1). (2-Methoxy-benzyl)-(6-nitro-quinolin-2-yl)-amine was obtained as a yellow solid (0.5 g, 42%), MS: m/e=310.5 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1>>[NH:35]1[C:32]2=[N:33][CH:34]=[C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:30]=[C:31]2[CH:37]=[CH:36]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cnc4[nH]ccc4c3)ccn2c1=O

Procedure:
Methyl 8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100.3 mg, 0.41 mmol).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[Br:9]Br>[OH-].[Na+]>[Br:9][N:5]1[CH2:4][CH:3]([CH2:2][Cl:1])[O:7][C:6]1=[O:8]
Reactant: BrBr
Reactant: O=C1NCC(CCl)O1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OC(CCl)CN1Br
Temperature: 0 °C

Procedure:
13.55 grams (0.1 mole) 5-chloromethyl-2-oxazolidinone, prepared in Example 1, were dissolved in 90 mL of a 1 M NaOH solution and then cooled to 0° C. 17.6 grams (0.11 moles) bromine were added dropwise, with stirring over a period of fifteen minutes. The product was extracted with methylene chloride. The extracts were then combined, dried and the solvent removed using a rotary evaporator to yield an orange solid. Proton NMR Data: δ3.15 (m, 1 proton), 3.48 (m, 1 proton), 3.7 (m, 2 protons), 4.7 (m, 1 proton) Elemental Analysis: Found (theory), C 24.05 (22.40), H 2.71 (2.35), N 6.98 (6.53), Cl 18.12 (16.53), Br 31.18 (37.26).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:36])([F:35])[C:11]([CH2:30][NH:31][CH2:32][CH2:33][CH3:34])([OH:29])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:32]([N:31]([CH2:30][C:11]([OH:29])([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]([F:36])([F:35])[F:9])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH2:33][CH3:34]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccsc1
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 1 from 3-thiophenecarboxylic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][CH:12]=3)[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[OH:1][C:2]1[CH2:3][CH2:4][C:5]([OH:21])=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)[C:7]2=[O:20]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1c(O)ccc(O)c1C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)C1=C(O)CCC(O)=C1C2=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1,4-Dihydroxy-anthraquinone-6-carboxylic acid (1.5 g) is mixed with Zn dust (3 g) in 300 mL glacial Acetic acid. The mixture is heated to 100° C. for 2 hours, filtered through Celite concentrated to half volume and added 250 mL water and placed at 5° C. overnight. The precipitate is collected by filtration. Yield: 1.1 g.