Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[C:17]=2[CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]4[C:47]([C:48]([OH:50])=[O:49])=[CH:46][S:45][C:44]=4[CH:51]=3)=[C:36]([CH3:52])[CH:35]=2)[CH2:15][CH2:14]1.CI.[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[CH:13]1([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:29])([F:30])[F:31])[C:17]=2[CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]4[C:47]([C:48]([OH:50])=[O:49])=[C:46]([CH3:1])[S:45][C:44]=4[CH:51]=3)=[C:36]([CH3:52])[CH:35]=2)[CH2:15][CH2:14]1
Reactant: Cc1cc(OCc2c(-c3ccccc3OC(F)(F)F)noc2C2CC2)ccc1-c1ccc2c(C(=O)O)csc2c1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1cc(OCc2c(-c3ccccc3OC(F)(F)F)noc2C2CC2)ccc1-c1ccc2c(C(=O)O)c(C)sc2c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 21.4 %

Procedure:
A solution of diisopropylamine (120 μL, 0.849 mmol) and THF (4 mL) is cooled to −78° C. A solution of n-butyl lithium (1.6 M in hexanes, 487 μL, 0.779 mmol) is added dropwise and the reaction is stirred for 40 minutes at −78° C. A solution of 6-{4-[5-cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3-carboxylic acid (200 mg, 0.354 mmol) in THF (2 mL) is added dropwise and the resulting yellow solution is stirred at −78° C. for one hour. Methyl iodide (221 μL, 3.54 mmol) is added dropwise and the reaction is allowed to gradually warm to ambient temperature overnight. The flask is cooled in an ice bath and saturated aqueous ammonium chloride (5 mL) is added. The mixture is diluted with water and ethyl acetate. The ethyl acetate layer is washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue is purified via radial chromatography eluting with 2% MeOH—CH2Cl2. The purification is repeated for impure fractions containing product. The title compound (44 mg, 21%) is obtained as a gray solid.
Reaction SMILES: [O:1]([CH:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Br-].[Li+].[H-].[Al+3].[Li+].[H-].[H-].[H-].COC(C)(C)C>C1(C)C=CC=CC=1>[Si:2]([O:1][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mechanically stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (501 mg, 2.36 mmol) in anhydrous toluene (10 mL) under an atmosphere of argon is treated with lithium bromide (1.06 g, 12.2 mmol). The mixture is cooled to -20° C. with an ice/salt bath and treated with lithium aluminum hydride (92.0 mg, 2.42 mmol) in one portion followed by tert-butyl methyl ether (1.0 mL). The ice/salt bath is replaced with an ice bath and the reaction is then stirred for 2 hours at 0° C. It is then quenched by slow addition of aqueous sodium hydroxide (1N, 7.0 mL) at a rate that maintains the temperature of the reaction below 20° C. The resulting suspension is then filtered through a pad of diatomaceous earth and the pad is subsequently rinsed with toluene. The filtrate phases are separated and the aqueous phase is extracted with toluene. The organic phase and organic extract are combined, rinsed with aqueous sodium hydroxide (1N), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg). The residue is then purified by Kugelrohr distillation (60°-80° C., 1 mmHg) to provide the title compound (350 mg, 69% yield) as a colorless oil; cis/trans/l-2+l-4 addition, 92.7/6.3/1.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11][CH2:12][CH2:13]Br.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccc(Br)cc1
Reaction time: 24 h
Yield: 95.3 %

Procedure:
In 100 ml of dimethylsulfoxide was dissolved 17.3 g (100.0 mmol) of 4-bromophenol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 4.0 g/25 ml) was added thereto. The resultant mixture was stirred until dissolving homogeneously. Next was added 12.3 g (100.0 mmol) of n-propyl bromide to the resultant mixture, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into an iced water, and the resultant oil was extracted with hexane. After the hexane phase was washed with water, hexane was removed from the hexane phase to give 20.5 g (95.3 mmol) of 1-bromo-4-n-propyloxybenzene.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3C=CC=[C:25](Cl)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][SH:3])[CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc(CCCN2CCN(c3cccc(Cl)c3)CC2)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: SCCCN1CCN(CCCc2ccc(Cl)cc2)CC1
Yield: 134.8 %

Procedure:
The procedure described in Example 1(b) was followed, using 7.6 g of thiourea, 22.9 g of 1-[3-(4-chlorophenyl)propyl]-4-(3-chlorophenyl)piperazine dihydrochloride, 5.8 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 14.1 g (65% of theory) of 3-{4-[3-(4-chlorophenyl)propyl]piperazin-1-yl}propanethiol dihydrochloride as a white crystalline solid, M.p. 238°-242° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[CH3:33][C:34]1[C:38]([S:39](Cl)(=[O:41])=[O:40])=[C:37]([CH3:43])[O:36][N:35]=1>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][S:39]([C:38]3[C:34]([CH3:33])=[N:35][O:36][C:37]=3[CH3:43])(=[O:41])=[O:40])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OS(=O)(=O)c3c(C)noc3C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 3,5-dimethylisoxazole-4-sulfonyl chloride (27 mg) in pyridine (2 ml) was performed according to the method described in example 58.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([C@H:13]([CH:15]1[CH2:17][CH2:16]1)[CH3:14])[CH2:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])#[CH:38].[SiH4]>C(NC(C)C)(C)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[Cl:11][C:9]1[CH:10]=[C:2]([C:38]#[C:37][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([C@H:13]([CH:15]1[CH2:17][CH2:16]1)[CH3:14])[CH2:5]2
Reactant: C#C[Si](C)(C)C
Reactant: C[C@@H](C1CC1)N1Cc2cc(Br)cc(Cl)c2C1=O
Agent: Cl[Pd]Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: C[C@@H](C1CC1)N1Cc2cc(C#C[Si](C)(C)C)cc(Cl)c2C1=O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
5-bromo-7-chloro-2-((S)-1-cyclopropylethyl)isoindolin-1-one (5.0 g, 15.89 mmol) was placed in a 3-neck flask, fitted with an internal thermocouple and dissolved in 150 mL of degassed diisopropyl amine. To this solution was added copper (II) acetate (0.14 g, 0.79 mmol), triphenylphosphine (0.417 g, 1.59 mmol) and bis(benzonitrile)dichloropalladium (II) (0.30 g, 0.79 mmol). Finally, ethynyltrimethylsilane (4.84 mL, 34.96 mmol) was added dropwise over a 20-min period. After the addition of the silane was complete, the reaction mixture was heated to and held at 65° C. until starting material was consumed (as monitored by LC/MS). The reaction was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The material was then filtered through a glass frit and the remaining solids in the frit were rinsed with diethyl ether. The volatiles were again removed under reduced pressure and the concentrated residue was purified by flash chromatography on silica gel eluting with 0 to 40% ethyl acetate in hexane. This afforded the title compound as a tan solid (4.90 g, 93%). 1H NMR (300 MHz, CDCl3) δ ppm 0.18-0.22 (m, 9H) 0.29-0.43 (m, 3H) 0.53-0.62 (m, 1H) 0.88-1.01 (m, 1H) 1.27 (d, 3H) 3.69 (dq, 1H) 4.33 (q, 2H) 7.35 (d, 1H) 7.42 (s, 1H). MS ESI, m/z=332 (M+H). HPLC Method A: 1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[C:15]([F:23])[C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37](O)=O)=[CH:33][C:32]=1[C:40]([F:43])([F:42])[F:41].C(Cl)CCl>C(#N)C.N1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([C:19]2[N:20]=[C:37]([C:34]3[CH:35]=[CH:36][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])=[C:32]([C:40]([F:41])([F:43])[F:42])[CH:33]=3)[O:22][N:21]=2)[CH:16]=[C:15]([F:23])[C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CN(CC(=O)OC(C)(C)C)Cc1c(F)cc(C(N)=NO)cc1F
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClCCCl
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cc(F)c(CN(C)CC(=O)OC(C)(C)C)c(F)c3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 76 (0.148 g, 0.45 mmol) and Intermediate 5 (0.107 mg, 0.375 mmol) in ACN (2.5 mL) was added EDC (0.101 g, 0.53 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2.5 mL) and heated at 150° C. in the microwave for 30 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.62 (1H, d, J=1.7 Hz), 8.39 (1H, dd, J=8.0, 1.7 Hz), 7.76 (2H, d, J=7.1 Hz), 7.49 (1H, d, J=8.0 Hz), 7.38-7.22 (3H, m), 7.15 (1H, d, J=7.6 Hz), 3.99 (2H, s), 3.25 (2H, s), 2.45 (3H, s), 2.07 (3H, s), 1.50 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14](C(OC)=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]cc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 0.386 g (1 mmole) of 8-chloro-1,2-dihydro-6-(2-fluorophenyl)-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 10 ml of methanol, 1 ml of water and 0.225 g (4 mmole) of potassium hydroxide was heated to reflux for 31/2 hours under an atmosphere of nitrogen. The solvent was evaporated and the residue was acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated and the residue was heated in mineral oil up to 230° for 5 min. The reaction mixture was partitioned between 1N hydrochloric acid and methylene chloride/hexane. The acid extract was made alkaline with sodium carbonate solution and extracted with methylene chloride. The residue obtained after evaporation of the dried extracts was chromatographed over 10 g of silica gel using methylene chloride/ethyl acetate 1:2. Crystallization of the combined clean fractions from ethyl acetate/hexane yielded colorless crystals with mp 247°-250°. Uv λ max 212 mμ (ε=42250) sh 262 (10000) ir (KBr) 1695 cm-1 (CO) 3150 (NH). Nmr (CDCl3) 4.18 ppm (d, 1) and 4.88 (d, 1) (AB-system, J=12.5 Hz, C4 -H) 6.28 (d, 1, J=2 Hz, C3 -H) 6.9-7.7 (m, 5, aromatic H) 8.13 (d, 1, J=8.5 Hz, C10 -H) 10.46 (broad s, 1, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NCc2ccccc2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and benzyl amine (0.5 ml, 4.5 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C22H22BN3O5S): 451.14. MS found (ESI negative): (M−H)−=450.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.78 (s, 1H), 9.15 (br, 1H), 8.38 (t, J=6 Hz, 1H), 7.37 (d, J=1.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.30-7.10 (m, 6H), 7.01 (dd, J=8.4 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 6.30 (dd, J=8.4 Hz, 1H), 4.80 (s, 2H), 4.25 (d, J=5.6 Hz, 1H), 3.79 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1.O>CN(C=O)C>[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc2nc(C(=O)Nc3nc4cc(-c5cccc(C(F)(F)F)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxy-ethanol (0.013 mL) in dry DMF (0.25 mL), sodium hydride (8 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (30 mg) was added to the reaction mixture, and the mixture was warmed to 70° C. The reaction was monitored by LCMS for 1 hour until substantially complete. After cooling the reaction mixture, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, the product was purified by column chromatography (pre-packed silica column) using a gradient of 0 to 6% 2M ammonia-methanol in DCM. 20 mg of 6-(2-methoxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 497.8. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (1H, s) 8.14 (1H, d) 7.93-8.03 (2H, m) 7.83 (1H, s) 7.67-7.74 (2H, m) 7.57-7.63 (1H, m) 7.51 (1H, dd) 7.10 (1H, d) 4.42-4.49 (2H, m) 3.70-3.76 (2H, m) 3.32-3.34 (3H, m).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:16]3[CH2:17][CH2:18][N:19]4[C@H:23]([C:24]=3[N:25]=2)[CH2:22][CH2:21][C:20]4=[O:26])=[CH:9][CH:8]=1)=[O:5])[CH3:2].ClC1N=C(N2CCOCC2)C2CCN3C(C=2N=1)CCC3=O.B(O)O.C([O-])(=O)C.[K+].C(#N)C>O.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>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:16]3[CH2:17][CH2:18][N:19]4[C@@H:23]([C:24]=3[N:25]=2)[CH2:22][CH2:21][C:20]4=[O:26])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN2C(=O)CC[C@@H]32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C1CCC2c3nc(Cl)nc(N4CCOCC4)c3CCN12
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN2C(=O)CC[C@H]32)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
and (S)-1-ethyl-3-(4-(4-morpholino-8-oxo-5,6,8,9,10,10a-hexahydropyrimido[5,4-g]indolizin-2-yl)phenyl)urea (xl2): 2-Chloro-4-morpholino-5,6,10,10a-tetrahydropyrimido[5,4-g]indolizin-8(9H)-one (0.232 g, 0.000751 mol), [4-Ethylureido)phenyl]boronic acid, pinacol ester (0.284 g, 0.000979 mol), Tetrakis(triphenylphosphine)palladium(0) (0.0541 g, 0.0000468 mol) Sodium carbonate (0.122 g, 0.00115 mol) and Potassium acetate (0.118 g, 0.00120 mol) were combined, nitrogen purged three times, added dry Acetonitrile (6.00 mL, 0.115 mol) followed by deoxygenated Water (3.80 mL, 0.211 mol), heated at 90° C. and stirred overnight. The reaction mixture was diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, chromatographed through silica gel (12 g, 0-50% EtOAc in heptane followed by 5% MeOH in dichloromethane), purified by HPLC, and the enantiomers were separated out by SFC. Enantiomer 1 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.20 (d, J=8.7, 2H), 7.49 (d, J=8.8, 2H), 6.15 (t, J=5.5, 1H), 4.68 (t, J=8.2, 1H), 4.11 (dd, J=12.4, 5.0, 1H), 3.78 (dd, J=8.9, 6.2, 2H), 3.71-3.62 (m, 2H), 3.61-3.50 (m, 2H), 3.31 (m, 2H), 3.18-3.05 (m, 2H), 2.91 (t, J=10.2, 1H), 2.84-2.71 (m, 1H), 2.70-2.59 (m, 1H), 2.57-2.43 (m, 2H), 2.35-2.22 (m, 1H), 1.93-1.80 (m, 1H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+437.2 (M+H)+; Enantiomer 2 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.20 (d, J=8.7, 2H), 7.49 (d, J=8.7, 2H), 6.15 (t, J=5.4, 1H), 4.68 (t, J=8.0, 1H), 4.11 (dd, J=12.6, 5.3, 1H), 3.78 (dd, J=8.8, 6.3, 2H), 3.73-3.61 (m, 2H), 3.56 (dd, J=11.9, 5.3, 2H), 3.31 (m, 2H), 3.18-3.06 (m, 2H), 2.91 (t, J=12.3, 1H), 2.83-2.71 (m, 1H), 2.70-2.59 (m, 1H), 2.59-2.42 (m, 2H), 2.37-2.21 (m, 1H), 1.94-1.79 (m, 1H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+437.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:44])[NH:14][C:15]([C:17]1[S:18][C:19]([S:42][CH3:43])=[C:20]([S:22]([C:25]2[CH:26]=[C:27]([C:31]3[C:36]([NH2:37])=[CH:35][C:34]([N+:38]([O-])=O)=[CH:33][C:32]=3[CH3:41])[CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:21]=1)=[NH:16])([CH3:11])([CH3:10])[CH3:9].[CH2:45]([O:47][C:48](=[O:62])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59](Cl)=[O:60])C.C([O-])(O)=O.[Na+].[NH4+].[Cl-]>C(Cl)Cl.[Cl-].[Na+].O.CCO.[Fe].CCOC(C)=O>[CH3:45][O:47][C:48](=[O:62])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59](=[O:60])[NH:37][C:36]1[CH:35]=[C:34]([NH2:38])[CH:33]=[C:32]([CH3:41])[C:31]=1[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([S:22]([C:20]2[CH:21]=[C:17]([C:15]([NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:44])=[NH:16])[S:18][C:19]=2[S:42][CH3:43])(=[O:24])=[O:23])[CH:26]=1
Reactant: CCOC(=O)CCCCCCCCCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCC(=O)Nc1cc(N)cc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Triethylamine (139 μL, 1 mmol) was added to a solution of {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 118 mg, 0.21 mmol) in DCM (10 mL). 11-chlorocarbonyl-undecanoic acid ethyl ester (73 mg, 0.26 mmol) was added dropwise over 5 min. After 30 minutes of stirring, the reaction was not complete. Additional portions of acid chloride (3×1 eq) were added in a similar manner, until the reaction was complete. Addition of EtOAc (40 mL) followed by aqueous workup with NaHCO3 (2×20 mL) and brine (30 mL) yielded the crude amide (206 mg) as a glass. The residue was dissolved in EtOH (5 mL) and 4M aq NH4Cl (1 mL) was added. Iron powder (165 mg, 3 mmol) was added and the reaction was heated at 75° C. for 1 h. The cooled mixture was filtered through a 0.22 μm filter and solids washed with 5 mL portions of MeOH and EtOAc. Additional EtOAc (80 mL) was added and the organic solution was washed with citric acid (2×20 mL), NaHCO3 (2×30 mL), water (30 mL), and brine (50 mL). Drying and concentration of the solution yielded the title compound (165 mg) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2
Reactant: OCc1ccc2cc(Br)ccc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc2cc(Br)ccc2c1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 6-bromo-2-naphthylmethyl alcohol (6.71 g, 28.3 mmol) in CH2Cl2 (350 mL) was added pyridinium chlorochromate (6.71 g, 31.13 mmol) all at once. The mixture visually went from orange-red to black over 30 minutes and 150 mL of ether was added. The black mixture was passed through a silica gel column and eluted with ether. The solvents were evaporated and the solid was further purified on silica gel (hexane:CH2Cl2 1:1) to give 6.25 g of 6-bromo-2-naphthaldehyde (94%) as a white solid. %). 1H NMR (300 MHz; CDCl3): δ 7.65 (dd, J1=2.0 Hz, J2=9.0 Hz, 1H); 7.84 (t, J=8.0 Hz, 2H); 7.97 (dd, J1=2.0 Hz, J2=8.0 Hz, 1H); 8.06 (d, J=2.0 Hz, 1H); 8.29 (s, 1H); 10.14 (s, 1H); 13C NMR (300 MHz; CDCl3): ppm 123.5, 123.9, 128.0, 130.1, 130.5, 130.8, 130.9, 133.9, 134.2, 137.1, 191.6.