Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.Br[C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:28][CH:29]=1.[C:36]1([C:42]2[O:43][CH:44]=[CH:45][N:46]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(=O)([O-])[O-].[Ag+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:36]1([C:42]2[O:43][C:44]([C:24]3[CH:25]=[N:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:28][CH:29]=3)=[CH:45][N:46]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Brc1cnc(-c2ccccc2)nc1
Reactant: c1ccc(-c2ncco2)cc1
Agent: Cl[Pd]Cl
Agent: [Ag+2]
Agent: [Fe+2]
Solvent: ClCCl
Solvent: O
Product: c1ccc(-c2ncc(-c3cnc(-c4ccccc4)o3)cn2)cc1
Temperature: 60 °C
Yield: 11 %

Procedure:
Silver carbonate (317 mg, 1.15 mmol), triphenylphosphine (16 mg, 0.06 mmol) and Pd(dppf)Cl2.CH2Cl2 (24 mg, 5 mole %) were stirred together at room temperature under nitrogen. 5-Bromo-2-phenylpyrimidine (163 mg, 0.69 mmol) was added followed by 2-phenyl-oxazole (84 mg, 0.58 mmol; prepared according to Ohnmacht, S. A. et al., Chemical Communications, 2008, 1241-1243). Finally water (6 mL) was added and the mixture heated for 18 hours at 60° C. The mixture was cooled to room temperature and filtered through Celite washing with DCM and acetone. Purification by silica gel flash chromatography (100% DCM) through a 12-g Silicycle® flash silica cartridge gave title compound as light yellow solid (19 mg, 11% yield); Rf 0.68 with DCM; melting point 228-231° C.; 1H-NMR (300 MHz; DMSO-d6) δ 9.39 (s, 2H), 8.45 (dd, 2H), 8.17 (dd, 2H), 8.11 (s, 1H), 7.54-7.65 (m, 6H); MS (ESI+) m/z 300 (M+1), (ESI−) m/z 298 (M−1); H-PGDS FPBA IC50: 125 μM.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO.C(OCC)(=O)C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([CH2:14][NH:11][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)=[CH:13][CH:12]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(C2=CCCCC2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2ccc(C3=CCCCC3)cc2)cc1
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 4-cyclohexenylaniline (3,40 g, 0.023 mol) and methyl 4-formylbenzoate (3.77 g, 0.023 mol) in DCM (50 ml) and methanol (15 ml) was added a catalytic amount of acetic acid. After stirring the solution for 3 hours, Na(OAc)3BH (24 g, 0.115 mol) was added. The reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate (3×), brine (2×), dried over magnesium sulphate, filtered, and concentrated to give an orange solid. The crude product was introduced into a column of silica gel and eluted with ethyl acetate:hexane (5:95) to give 4-[(4-cyclohex-1-enylphenylamino)methyl]benzoic acid methyl ester (5 g, 0.015 mol).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:4][CH2:5][C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][OH:23])[CH:16]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.ClC1C=CC=C(Cl)C=1NCC1C(NC2C=[CH:46][CH:45]=[C:44]([CH2:48][CH2:49][OH:50])C=2)=NC(SC)=NC=1.BrC1C=CC=CC=1N.O1C=CCCC1>ClCCl.[Cl-].[Na+].O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:4][CH2:5][C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][O:23][CH:49]3[CH2:48][CH2:44][CH2:45][CH2:46][O:50]3)[CH:16]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CCO)c2)n1
Reactant: CSc1ncc(CNc2ccccc2Br)c(Nc2cccc(CCO)c2)n1
Agent: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Nc1ccccc1Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CSc1ncc(CNc2ccccc2Br)c(Nc2cccc(CCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3.5 g (7.9 mmol) of 5-(2-bromoanilino)methyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine (prepared in a method analogous to that for 5-(2,6-dichloroanilino)methyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine of Example 37(f) using 2-bromoaniline in place of 2,6-dichloroaniline) in 100 ml of dichloromethane was treated with 3.3 g (39 mmol) of 2,3-dihydropyran and 15 mg (0.08 mmol) of toluenesulfonic acid monohydrate and the mixture stirred at room temperature for 3 days. Subsequently 100 ml of diethyl ether and 100 ml of brine were added. The mixture was separated and the organic phase dried over magnesium sulfate, filtered and evaporated. Flash chromatography on silica gel using diethyl ether and hexane in a ratio of 1:1 as eluent afforded 2.6 g of 5-(2-bromoanilino)methyl-4-[3-(2-(tetrahydropyranyloxy)ethyl)phenyl]amino-2-methylthiopyrimidine as a yellow oil. [Mass spectrum (ESI) MH+ =529].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]([C:20]#[N:21])=[C:6]([NH:8][C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[CH:7]=1.C1N(P(N2CC2)(N2CC2)=S)C1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:21][C:20]1[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[C:3]([N+:22]([O-:24])=[O:23])[CH:4]=2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cc(C)cc(CC(=O)Nc2cc(Cl)c([N+](=O)[O-])cc2C#N)c1
Agent: S=P(N1CC1)(N1CC1)N1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2c(N)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(5-chloro-2-cyano-4-nitrophenyl)-2-(3,5-dimethylphenyl)acetamide (prepared essentially as described in EXAMPLE 10, StepA, 250 mg in 7 mL N,N-dimethylformamide) was added 46 mg of 95% sodium hydride and the mixture stirred at room temperature. After 1.5 hours, the reaction mixture was diluted with ethyl acetate and quenched by the careful addition of 10% aqueous sodium bisulfate. The organics were then washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was suspended in methylene chloride and the solids collected by filtration and dried in vacuo to give the title compound (188 mg).
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](=[O:17])[CH3:16])=[CH:14][C:9]=2[N:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH:3]([CH3:5])[CH3:4].[Br:26]Br.C(OCC)C>C(O)(=O)C>[ClH:1].[Br:26][CH2:16][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:8][C:9]=2[CH:14]=1)=[O:17]
Reactant: COc1cccc(-c2nc3cc(C(C)=O)ccc3n2CC(C)C)c1
Reactant: BrBr
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cccc(-c2nc3cc(C(=O)CBr)ccc3n2CC(C)C)c1
Yield: 63.2 %

Procedure:
To a solution of 32.7 g (91.3 mM) of 1-[1-isobutyl-2-(3-methoxy phenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride in 330 ml of acetic acid are added dropwise 4.7 ml (91.4 mM) of bromine. 100 ml of diethyl ether are then added and the crystalline product is filtered off. It is washed with diethyl ether and dried under vacuum to give 35 g of 2-bromo-1-[1-isobutyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:29])([F:30])[F:31])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14]
Reactant: COc1cccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(=O)onc(C)c3c2)C(F)(F)F)c1Br
Solvent: ClC(Cl)Cl
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc(O)c3Br)C(F)(F)F)cc12

Procedure:
Example 25 is produced analogously to Example 24 starting from the corresponding (−)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one. Flash point 227–231° C., [α]D=−94.3° (c 0.5 in chloroform).
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][S:37]([C:40]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:41]=1[C:42](O)=[O:43])(=[O:39])=[O:38].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CO.C(OCC)(=O)C.ClCCl>[CH3:36][S:37]([C:40]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:41]=1[C:42]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:43])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4S(C)(=O)=O)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.53 g, 1.0 mmol) and dichloromethane (10 mL). Add 2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoic acid (0.27 g, 1.0 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), N,N-diisopropylethylamine (0.34 mL, 2.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2 mmol). After 18 hours, dilute the reaction mixture with ethyl acetate and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 2% methanol/ethyl acetate and then 5% methanol/ethyl acetate give the title compound: Rf=0.41 (silica gel, 10% methanol/ethyl acetate)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.B([C:29]1[CH:30]=[C:31]2[C:39](=[CH:40][CH:41]=1)[N:38]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:37]1[CH:36]=[C:35]3[C:48]([CH3:56])([CH3:55])[C:49]4[C:54]([C:34]3=[CH:33][C:32]2=1)=[CH:53][CH:52]=[CH:51][CH:50]=4)(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]1([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=[C:8]([C:4]3[CH:3]=[C:2]([C:29]4[CH:30]=[C:31]5[C:39](=[CH:40][CH:41]=4)[N:38]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:37]4[CH:36]=[C:35]6[C:48]([CH3:56])([CH3:55])[C:49]7[C:54]([C:34]6=[CH:33][C:32]5=4)=[CH:53][CH:52]=[CH:51][CH:50]=7)[CH:7]=[CH:6][CH:5]=3)[N:9]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(B(O)O)ccc4n(-c4ccccc4)c3cc21
Reactant: Brc1cccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5cccc(-c6nc(-c7ccccc7)cc(-c7ccccc7)n6)c5)ccc4n(-c4ccccc4)c3cc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
16 g (43.3 mmol) of 2-(3-bromophenyl)-4,6-diphenylpyrimidine 14 and 19.3 g (48 mmol) of 7-borono12,12-dimethyl-10-phenyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene 13 are dissolved in 80 ml of toluene and degassed. 281 ml of a degassed 2M K2CO3 and 2.5 g (2.2 mmol) of Pd(OAc)2 are added. The reaction mixture is subsequently stirred for 48 h at 80° C. under a protective-gas atmosphere. Additional toluene is added to the cooled solution, which is washed a number of times with water, dried and evaporated. The product is purified by column chromatography on silica gel with toluene/heptane (1:2). The purity is 99.9%. Yield: 22 g (31 mmol), 77% of theory.
Reaction SMILES: [F:1][CH:2](F)[CH2:3]I.[NH:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.N1CC[C@@H](NC(=O)OC(C)(C)C)C1>>[F:1][CH2:2][CH2:3][N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:7]1
Reactant: FC(F)CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCF)C1

Procedure:
The title compound was prepared by substituting 1-fluoro-2-iodoethane for 1,1-difluoro-2-iodoethane and (S)-tert-butyl pyrrolidin-3-ylcarbamate for (R)-tert-butyl pyrrolidin-3-ylcarbamate in EXAMPLE 180A.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[N+:2]=[N-:3].[H-].[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1.C(#N)C.O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)CC(=O)COCCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
A solution of 4-azidobutanol (6.8 g) in tetrahydrofuran (100 ml) was added dropwise over 30 minutes to a suspension of sodium hydride (5.4 g; 60% dispersion in oil) in tetrahydrofuran (100 ml). The mixture was stirred at room temperature for 30 minutes and then treated with a solution of ethyl 4-chloroacetoacetate (9.7 g) in tetrahydrofuran (150 ml) dropwise over 30 minutes. The mixture was stirred at room temperature for 16 hours, poured into water and the pH adjusted to 3-4 with 2M hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3×200 ml) and the organic layer was dried (MgSO4) and evaporated to give an oil which was taken up in acetonitrile and washed with petrol. The solvent was evaporated to dryness and the residue was chromatographed on silica eluting with a mixture of petrol and methylene chloride. Fractions containing the product were evaporated to give ethyl 4-(4-azidobutoxy)acetoacetate as a yellow oil (4.5 g). Methyl 3-aminocrotonate (2.2 g) and 2-chlorobenzaldehyde (2.7 g) in methanol (50 ml) were added and the mixture was heated under reflux for 5 hours and then evaporated. The residue was chromatographed on silica eluting with a mixture of petrol and ethyl acetate to give 2-(4-azidobutoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (5.9 g) as a yellow oil. The product was taken up in methanol (70 ml) and stirred at room temperature for 16 hours under 1 atmosphere of hydrogen in the presence of 5% palladium on calcium carbonate catalyst (2.0 g). The reaction mixture was filtered and concentrated. The residue was treated with a solution of fumaric acid (1.0 g) in methanol. The resulting precipitate was collected, treated with 2M ammonium hydroxide and extracted with methylene chloride (2×25 ml). The organic layer was washed with water, dried (MgSO4), filtered and evaporated to give 2-(4-aminobutoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (2.2 g) as a yellow oil. The product was used in the next stage without further purification.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12](=[O:21])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:12](=[O:21])[CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)Nc2ccccc2-1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)N(CCN(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0.1 M) of methyl 12-cyclohexyl-6-oxo-6,7-dihydro-5H-thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]benzodiazepine-10-carboxylate (from Step 4) in DMF was treated with sodium hydride (1.5 eq., 60% suspension in mineral oil) at 0° C. and then stirred at RT for 30 min. 2-Chloro-N,N-dimethylethylamine (2.0 eq.) was added and the solution stirred at 45° C. for 2 h. After cooling to RT, the suspension was diluted with EtOAc and washed with water, and brine. The organic phase was dried over sodium sulfate and the solvent evaporated in vacuo to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 8.14 (s, 1H), 7.74-7.45 (m, 4H), 5.04-5.01 (d, J 12, 1H), 4.43-4.40 (d, J 12, 1H), 4.18-4.15 (m, 1H), 3.83 (s, 3H), 3.65-3.61 (m, 1H), 2.90-2.82 (m, 1H), 2.15-2.06 (m, 2H), 1.81-1.23 (m, 10H). MS (ES+) m/z: 466 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[C:16]1([CH2:19][C:20](=[O:24])[C:21](O)=[O:22])[CH2:18][CH2:17]1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:31](=[O:32])[O:30][CH2:29]2.Cl>CC(N(C)C)=O.C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[C:16]1([CH2:19][C:20](=[O:24])[C:21]([NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:31](=[O:32])[O:30][CH2:29]3)=[O:22])[CH2:17][CH2:18]1
Reactant: O=C(O)C(=O)CC1(c2cc(C(F)(F)F)ccc2F)CC1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At −10° C., 0.84 ml of thionyl chloride are added to 2.9 g of 3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionic acid in 15 ml dimethylacetamide. The mixture is stirred for 30 min. at −10° C. and for 1 hour at 0° C. and then added to 1.95 g of 5-aminophthalide (or, vice versa, 5-aminophthalide may be added to the mixture). After 16 hours at ambient temperature, 2 M hydrochloric acid and ethyl acetate are added, the organic phase is washed to neutral with water, dried over sodium sulfate and concentrated. After chromatography on silica gel (hexane/ethyl acetate: 1+1) and recrystallization from diisopropyl ether, 2.4 g of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionylamino}-phthalide (m.p. 168° C.) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.Br.Br.[CH2:38]([C:40]1[C:41]([C:48]2[CH:56]=[C:55]3[C:51]([C:52]([C:57]4[NH:66][C:60]5[CH2:61][CH2:62][NH:63][CH2:64][CH2:65][C:59]=5[N:58]=4)=[N:53][NH:54]3)=[CH:50][CH:49]=2)=[CH:42][C:43]([F:47])=[C:44]([OH:46])[CH:45]=1)[CH3:39].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:63]2[CH2:62][CH2:61][C:60]3[N:66]=[C:57]([C:52]4[C:51]5[C:55](=[CH:56][C:48]([C:41]6[CH:42]=[C:43]([F:47])[C:44]([OH:46])=[CH:45][C:40]=6[CH2:38][CH3:39])=[CH:49][CH:50]=5)[NH:54][N:53]=4)[NH:58][C:59]=3[CH2:65][CH2:64]2)=[O:10])=[N:6][CH:7]=1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(Cl)cn3)CC4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a solution of 5-chloro-pyridine-2-carboxylic acid (13.2 mg, 85 μmol) in DMF (1 mL) was added HATU (32 mg, 85 μmol) and the resulting reaction mixture was stirred at room temperature for 30 minutes. 5-Ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) and DIPEA (56 μL, 320 μmol) were added and stirring was continued at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method A to afford 20.5 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][CH:9]2[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:16]=[C:17](Cl)[C:18]2[N:19]([C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([F:33])[CH:28]=3)=[O:25])=[CH:22][N:23]=2)[N:20]=1.BrC1C2N(C(C(NC3C=CN=C(F)C=3)=O)=CN=2)N=C(Cl)C=1.BrC1C2N(C(C(NC3C=CN=C(F)C=3)=O)=CN=2)N=C(Cl)C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:14][C:15]1[CH:16]=[C:17]([N:8]([CH:9]2[CH2:11][CH2:10]2)[CH2:7][C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:18]2[N:19]([C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([F:33])[CH:28]=3)=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: COc1ccc(CNC2CC2)cc1
Reactant: O=C(Nc1ccnc(F)c1)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(Nc1ccnc(F)c1)c1cnc2c(Br)cc(Cl)nn12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 78 %

Procedure:
N-(4-methoxybenzyl)cyclopropanamine (381 mg, 2.148 mmol) was added to ˜1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (467 mg, 1.432 mmol, example 13A) and DIEA (0.500 mL, 2.86 mmol) in DMF (10 mL). The reaction mixture was heated at 80° C. for 1.5 hrs. Water (20 mL) was added, and the solid was collected via Buchner filtration and dried under reduced pressure overnight to afford 6-Chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as a yellow solid (519 mg, 78%). The crude material was taken into the next step without further purification. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=2.22 minutes. [M+H]=467.21.
Reaction SMILES: [C:1](=[O:14])([O:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)[NH2:2].IC1C=CC=C(CC([O-])=O)C=1CC([O-])=O.[O-2].[Mg+2]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[C:4]123[CH2:5][CH:6]4[CH2:12][CH:10]([CH2:9][CH:8]([CH2:7]4)[CH:13]1[NH:2][C:1](=[O:14])[O:3]2)[CH2:11]3
Reactant: NC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: [Rh]
Agent: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1NC2C3CC4CC(C3)CC2(C4)O1
Yield: 77 %

Procedure:
Tricyclo[3.3.1.13,7]dec-1-yl carbamate (100 mg, 0.512 mmol), iodobenzenediacetate (220 mg, 0.683 mmol), magnesium oxide (50 mg, 1.24 mmol) and rhodium (II) acetate dimer (22 mg, 0.050 mmol) were stirred in dichloromethane (3 mL) at 50° C. for 5 hours. After completion of the reaction, the reaction solution was filtered, and the solid was washed with chloroform and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→2/1) to give the desired product (77% yield).