Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13](Br)[CH:12]=[C:11]([C:16]([NH2:18])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N>CN(C=O)C.CO.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].C(Cl)Cl.O.COCCOC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:27]4[CH:28]=[CH:29][C:30]([CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:38][CH:39]=4)[CH:12]=[C:11]([C:16]([NH2:18])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1[nH]c1cc(N)ccc12
Temperature: 100 °C
Yield: 50.9 %

Procedure:
A microwave vial containing 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxamide (150 mg, 0.393 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (238 mg, 0.787 mmol), PdCl2(dppf)-CH2Cl2 adduct (32 mg, 0.039 mmol) was flushed with nitrogen. DME (2 mL) and Na2CO3 (0.98 mL, 2.0 mmol, 2.0 N aq. solution) were added and the vial was sealed and heated at 100° C. for 2 hrs. This was diluted with DMF and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-amino-2-(4-(morpholinomethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (90 mg, 0.20 mmol, 51% yield) as a yellow solid. MS (ESI) m/z 402.16 (M+H); HPLC retention time of 0.87 min with Xbridge S10 4.6×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 95% MeOH—5% H2O—0.1% TFA; Solvent B: 5% MeOH—95% H2O—0.1% TFA.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH2:7]1[C:3]2([CH2:2][O:1][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[NH:8]2)[CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCC1
Reactant: NC1(CO)CCCC1
Solvent: Cc1ccccc1
Product: C1CCC2(C1)COC1(CCCC1)N2
Yield: 175.7 %

Procedure:
A solution of 1-hydroxymethylcyclopentanamine (Method B1c; 263 g, 2.3 mol) and cyclopentanone (220 mL, 1.3 mol, 1.1 equiv.) in toluene (2.7 L) was heated at the reflux temp. with azeotropic removal of water until the theoretical amount of water had been collected (41.4 mL). The reaction mixture was concentrated to 700 mL by simple distillation, then cooled to room temp. and concentrated to constant weight under reduced pressure to give 6-aza-12-oxadispiro[4.1.4.2]tridecane (414 g, 100%) as a pale yellow oil: 1H NMR (CDCl3) δ1.55-1.89 (m, 17H), 3.60 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: CCC(C)CCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(C)CCCCCOc1ccc(O)cc1

Procedure:
A flask was charged with 23.37 g of optically active 4-benzyloxyphenyl 6-methyloctyl ether, 2.33 g of 10% Pd/C and 230 ml of ethanol, and the mixture was reacted at room temperature until it reacted with a theoretical amount of hydrogen. After completion of the reaction, the catalyst was removed by filtration and the organic solvent was distilled under reduced pressure to obtain a crude product. The crude product was refined to obtain 16.91 g of the intended phenol.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3]1.[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[CH2:30]([O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[CH2:3][C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCO
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc2c(c1CCC)OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a mixture of 406 mg (1.00 mmol) of the title product of Example 1, 190 mg (1.20 mmol) of 1-decanol, and 393 mg (1.50 mmol) of triphenylphosphine in 10 ml of dimethylformamide was added 261 mg (1.50 mmol) of diethyl azodicarboxylate. After stirring overnight at room temperature, the solvent was removed under reduced pressure. Chromatography of the residue on silica gel, using 20% ethyl acetate/hexane as eluent, gave 408 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.[Cl-].[Na+]>CN(C=O)C>[CH:21]1([NH:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCC1
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C#N)c(NC2CCC2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (2 g, 10.8 mmol) in DMF (10 mL) was added DIEA (4.2 g, 32.4 mmol) and cyclobutanamine (2.3 g, 32.4 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into saturated sodium chloride, and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. The crude product was purified via silica gel column chromatography (10% ethyl acetate in petroleum ether) to get the desired product as a white solid (1.7 g, 7.7 mmol, 71% yield). MS (ESI) m/z=221.2[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24](OCC)=O)=[C:18]([Cl:29])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Bi](Cl)(Cl)Cl.[BH4-].[Na+].[BH4-].[K+].[Cl-].[Li+].CS(Cl)(=O)=O.[I-].[Na+].[N:47]([O-:49])=[O:48].[Na+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N+:47]([O-:49])=[O:48])=[C:18]([Cl:29])[CH:17]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)C=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Agent: CS(=O)(=O)Cl
Agent: Cl[Bi](Cl)Cl
Agent: [BH4-]
Product: O=[N+]([O-])CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl

Procedure:
The process of the present invention, which enables industrial scale production of Compound I, is carried out as follows (See also Scheme I): Ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate is reduced using bismuth trichloride and sodium borohydride. The reduced product is further reduced using potassium borohydride and lithium chloride. The resulting alcohol derivative is mesylated by reacting with methanesulfonyl chloride. The mesylated product is iodinated with sodium iodide and then reacted with sodium nitrite to form 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benzene. This product is reacted with formaldehyde in the presence of a base to form 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol. Reducing this compound with palladium hydroxide-carbon gives Compound I.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7][CH2:6]2)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7][CH2:6]2)#[N:2]
Reactant: CCOC(=O)/C=C/CC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Reaction time: 1.75 h
Yield: 99.4 %

Procedure:
To a solution of 1,1-dimethylethyl 6-cyano-1-[(2E)-4-(ethyloxy)-4-oxo-2-buten-1-yl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 25; 530 mg, 1.38 mmol) in ethanol (20 ml) under nitrogen was added palladium on carbon (106 mg, 0.100 mmol). The resulting mixture was stirred under an atmosphere of hydrogen (1 bar) for 105 min. The catalyst was filtered off through Celite® and the filtrate concentrated in vacuo to give the title compound (530 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH2:30])[CH3:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][CH3:32])[CH2:24][CH3:25])[N:7]=1
Reactant: CCN(CC)CCCN
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (1.59 g, 4.47 mmol) in dichloromethane (89.4 mL) were added N,N-diethyl-1,3-propanediamine (0.845 mL, 5.36 mol) and triethylamine (1.26 uL, 8.94 mmol). The mixture was stirred at rt overnight. Some white precipitate was formed during the reaction. Filtration followed by wash with ethyl acetate/dichloromethane/methanol afforded the title compound (1.028 g, 60%). LC-MS m/z 383 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O.CO[CH2:28][CH2:29]OC>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>[CH:28]([C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)=[CH2:29]
Reactant: O=S(=O)(Oc1cc2c(nn1)OCCC2)C(F)(F)F
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1cc2c(nn1)OCCC2
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Argon was bubbled for 15 minutes through a solution of 6,7-dihydro-5H-pyrano[2,3-c]pyridazin-3-yl trifluoromethanesulfonate (228 mg, 0.8 mmol) in 1,2-dimethoxyethane (6.5 ml). Tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.0475 mmol) was added and the solution stirred for 20 minutes under argon. The mixture was then treated with potassium carbonate (111 mg, 0.8 mmol), water (1.9 ml) and triethenylboroxin pyridine complex (180 mg, 0.75 mmol). After stirring for 2 hours at 80° C., the mixture was cooled and partitioned between DCM and saturated aqueous sodium bicarbonate solution. Layers were separated and the aqueous was extracted twice with 20% MeOH/DCM. The combined organic solution was dried over magnesium sulfate, evaporated and the residue chromatographed on silica, eluting with ethyl acetate to give the product as a white solid (100 mg, 77%).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:9][N:10]=2)[N:7]=1.[O-:19][CH2:20][CH3:21].[Na+].O>C(O)C>[CH2:20]([O:19][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:9][N:10]=2)[N:7]=1)[CH3:21]
Reactant: Cc1c(Cl)nn2c(NCC(F)(F)F)nnc2c1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nn2c(NCC(F)(F)F)nnc2c(C)c1C
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
(6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(2,2,2-trifluoroethyl)amine (W2.150; 330 mg) was initially charged in ethanol (25 ml) and admixed with sodium ethoxide (90 mg). The reaction mixture was stirred at 50° C. for 4 h, then further sodium ethoxide (10 mg) was added and the mixture was stirred further at 50° C. for 3 h. After standing overnight, the mixture was admixed with water and dried. The residue was taken up in EA and washed three times with water. The EA phase was dried over sodium sulfate, filtered and concentrated. 340 mg of the title compound were obtained. LC-MS rt: 0.82 min [M+H]+: 290.2 (met. b)
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:5](=[O:29])[NH:6]2.N(OCCC(C)C)=O.C(#N)C.O.C(O)=O.[I:50]CI>>[F:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]3[N:8]=[C:7]4[C:3]([N:4]([CH2:30][C:31]([F:33])([F:34])[F:32])[C:5](=[O:29])[NH:6]4)=[C:2]([I:50])[N:10]=3)=[N:12][N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:14]2=[N:15][CH:16]=1
Reactant: ICI
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc2[nH]c(=O)n(CC(F)(F)F)c12
Agent: CC(C)CCON=O
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c2n1CC(F)(F)F
Temperature: 85 °C

Procedure:
4.650 g (5.954 mmol) of the compound from example 62 were dissolved in 12 ml of diiodomethane and admixed with 12.76 ml (95.270 mmol) of isopentyl nitrite. The reaction mixture was heated to 85° C. for 16 h and, after cooling, concentrated on a rotary evaporator. 5 g of the crude product (purity 54%) were obtained. 1.2 g of the residue were by means of preparative HPLC (eluent: acetonitrile/water with 0.05% formic acid, gradient 40:60→95:5). 128 mg of the title compound were obtained (15% of theory).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[C:14]([NH2:15])[N:4]2[N:3]=1.[O-:16][CH2:17][CH3:18].[Na+]>C(O)C>[CH2:17]([O:16][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[C:14]([NH2:15])[N:4]2[N:3]=1)[CH3:18]
Reactant: CC[O-]
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCCC3
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c2c1CCCC2
Yield: 47.1 %

Procedure:
6-Chloro-7,8,9,10-tetrahydro-[1,2,4]triazolo[3,4-a]phthalazin-3-ylamine (W2.018, 1.0 g) was dissolved in ethanol (50 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (1.34 g) and stirred at 60° C. for 1 h. After the solvent had been drawn off, the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 491 mg of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[I-:16].[K+].II.Cl>[OH-].[NH4+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:7]=1[I:16]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: [I-]
Agent: Cl
Agent: II
Agent: [K+]
Solvent: O
Product: O=C(c1ccccc1)c1ccc(O)c(I)c1
Reaction time: 0.5 h

Procedure:
A solution of (4-hydroxyphenyl)(phenyl)methanone (2.0 g, 10 mmol) in saturated aqueous ammonium hydroxide (130 mL) was stirred at 25° C. for 15 min, and then treated with a solution of potassium iodide (8.2 g, 49 mmol) and iodine (2.6 g, 10 mmol) in water (260 mL). After 30 min, the mixture was adjusted to pH 2 with concentrated aqueous HCl and extracted with EtOAc (500 mL). The organic extract was sequentially washed with sat. aqueous sodium thiosulfate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 40 g, 0->80% EtOAc/hexanes) gave (4-hydroxy-3-iodophenyl)(phenyl)methanone as a white solid. MS (ESI) m/z: Calculated: 324.0; Observed: 325 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10](Cl)(=[O:12])=[O:11])=[C:5]([O:14][CH3:15])[CH:4]=1)#[N:2].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[Br:16])(=[O:12])=[O:11])=[C:5]([O:14][CH3:15])[CH:4]=1)#[N:2]
Reactant: Nc1ccccc1Br
Reactant: COc1cc(C#N)ccc1NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1NS(=O)(=O)Nc1ccccc1Br

Procedure:
To a solution of N-(4-cyano-2-methoxyphenyl)-sulfamoyl chloride (1 mmol) in DMF (1 mL) is added 2-bromoaniline (1 mmol). Upon completion of the reaction, an aqueous work up is performed. The crude material will be purified by either recrystalization or chromatography to give N-(4-Cyano-2-methoxyphenyl)-N′-(2-bromophenyl) sulfamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(=O)(O)[O-].[Na+].O1[CH2:38][CH2:37]OCC1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:38][CH2:37][N:3]([CH3:4])[CH2:2][CH2:7]3)[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Reactant: C1COCCO1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N3CCN(C)CC3)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (105 mg, 0.28 mmol, Example 120) and sodium bicarbonate (84 mg, 1 mmol) in 1,4-dioxane (3 mL), bis-2-chloroethyl-methylamine hydrochloride (58 mg, 0.30 mmol, Aldrich) was added and the mixture was stirred at reflux overnight. An additional 20 mg of bis-2-chloroethyl-methylamine hydrochloride (Aldrich) was added and the reaction was refluxed for another 12 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×10 mL) and the extracts were dried with sodium sulfate. Removal of solvent gave a yellow solid which was chromatographed (8% 9N ammonia in methanol/dichloromethane) to give a pale yellow solid. 16 mg, 12%. MS (ES) MH+=461.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9]O)=[CH:5][CH:4]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][C:17]23[CH:21]=[CH:22][CH:23]=[CH:24][CH:16]2[C:15]([NH:19][C:18]3=[O:20])=[O:25])=[CH:5][CH:4]=1
Reactant: OCC=Cc1ccc(C(F)(F)F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(CC=Cc3ccc(C(F)(F)F)cc3)C=CC=CC12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
4-(Trifluoromethyl)cinnamyl alcohol (3 g, 14.84 mmol) was dissolved in THF (60 ml), and phthalimide (2.84 g, 19.29 mmol) and triphenylphosphine (5.84 g, 22.26 mmol) were added to the solution, to which a solution of diethyl azodicarboxylate (3.87 g, 22.26 mmol) in THF (20 ml) was gradually added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/methylene chloride=1/1) to afford 2-[3-(4-trifluoromethylphenyl)-2-propenyl]phthalimide (4.57 g, yield 93%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[C:25](OC)([CH3:27])[CH3:26].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]2[CH2:20][O:21][C:25]([CH3:27])([CH3:26])[O:22]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: O=S(=O)(c1ccc(Cl)nc1)N(CC(O)CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CN(c2ccccc2)S(=O)(=O)c2ccc(Cl)nc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A mixture of 0.67 g (1.96 mmol) of 6-chloro-N-(2,3-dihydroxypropyl)-N-phenylpyridine-3-sulfonamide, 0.53 mL (4.3 mmol) of 2,2-dimethoxypropane and 37 mg of pTsOH in 4 mL of DMF is stirred for 3 hours at room temperature. The medium is taken up in 100 mL of EtOAc, washed with 50 mL of saturated NaHCO3 solution and 50 mL of water and then dried over Na2SO4, filtered and concentrated under reduced pressure. 0.54 g 6-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-N-phenylpyridine-3-sulfonamide is obtained in the form of a brown solid, which is used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:24])[CH2:13]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:24])[CH2:13][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)C[C@@H](O)c2cccc3c(C)c(C)oc23)cc1
Product: CCN(CC)C[C@@H](O)c1cccc2c(C)c(C)oc12
Yield: 527.3 %

Procedure:
15 g (41.65 mmol) of (+)-2,3-dimethyl-7-(2-para-methylphenylsulphonyl-1(S)-hydroxyethyl)benzofuran and 210 ml (2.03 mol) of diethylamine are introduced into a 500 ml three-necked flask equipped with a stirrer and a reflux condenser. The solution is stirred at reflux for 16 h and the solution is concentrated. The residue is purified by successive column chromatography operations (elution solvent: 90/10 dichloromethane/methanol) and dried in a desiccator under vacuum over phosphorus pentoxide. 57.4 g of (+)-2,3-dimethyl-7-(2-diethylamino-1(S)-hydroxyethyl)benzofuran are obtained in the wax form -[α]D20 =+94.7° (c=1, methanol). The enantiomeric excess is 98.5%.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])=[N:4][C:3]=1[C:21](OCC)=[O:22].[BH4-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])=[O:20])=[N:4][C:3]=1[CH2:21][OH:22]
Reactant: CCOC(=O)c1nc(NC(=O)NS(=O)(=O)c2cccc(C)c2)sc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)NC(=O)Nc2nc(CO)c(Br)s2)c1
Yield: 47 %

Procedure:
Ethyl 5-bromo-2-({[(3-methylphenyl)sulfonyl]carbamoyl}amino)-1,3-thiazole-4-carboxylate (50 mg, 0.11 mmol) was treated with sodium borohydride (21 mg, 0.56 mmol) in tetrahydrofuran (2 ml) for 2 days at room temp. 0.5 M HCl was added and the quenched reaction mixture was purified on preparative HPLC yielding 21 mg of the title compound as an amorphous solid. MS (ES): m/e 404.1 (M−H)
Reaction SMILES: O[C:2]1([C:11]2[N:12](S(C3C=CC=CC=3)(=O)=O)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH:7]2[N:9]([CH3:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:2]1[CH2:8][CH:7]2[N:9]([CH3:10])[CH:4]([CH2:5][CH2:6]2)[CH:3]=1
Reactant: CN1C2CCC1CC(O)(c1cc3ccccc3n1S(=O)(=O)c1ccccc1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C2C=C(c3cc4ccccc4[nH]3)CC1CC2

Procedure:
A solution of 3-hydroxy-3-(1-phenylsulfonylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane and trifluoroacetic acid in dichloromethane is stirred at room temperature until the dehydration is complete. The reaction mixture is concentrated under reduced pressure and the residue partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is separated, washed well with water, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to provide the desired compound.