Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[O:10][C:11]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[N:12][N:13]=1)(=O)[NH2:7].O>N1C=CC=CC=1>[C:6]([C:9]1[O:10][C:11]([C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[N:12][N:13]=1)#[N:7]
Reactant: Cc1cc(C)cc(-c2nnc(C(N)=O)o2)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2nnc(C#N)o2)c1
Reaction time: 4 h

Procedure:
200 g of phosphorus oxychloride are added to a suspension of 189.5 g of 2-carbamoyl-5-(3,5-dimethylphenyl)-1,3,4-oxadiazole in 873 cm3 of anhydrous pyridine, in the course of one hour and whilst stirring. During this addition, the temperature of the reaction medium rises from 20° to 42° C. The stirring is continued for 4 hours, whilst allowing the temperature of the medium to return to 20° C. The reaction mixture is then poured into 8.7 liters of water and the precipitate which forms is filtered off, washed twice with 500 cm3 of water and then dried in the air. After recrystallization from isopropanol, 163 g of solid 2-cyano-5-(3,5-dimethylphenyl)-1,3,4-oxadiazole, which melts at 127° C., are obtained.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1.CCOCC>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([O:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[N:12]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(O)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(Oc1cncc(Cl)n1)c1ccccc1
Reaction time: 0.17 h

Procedure:
K-t-BuO (2.1 g, 18.7 mmol) was added to a stirred solution of 1-phenyl-1-ethanol (2.45 g, 20.1 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After 10 min of stirring, 2,6-dichloropyrazine (2.49 g, 16.7 mmol) was added whereupon the reaction mixture turned orange colored. After being stirrred for a further 1.5 h, ether was added and the mixture was filtered. Concentration in vacuo furnished an orange colored oil that was purified by silica gel chromatography (15×5 cm) using n-hexane ethyl acetate (9:1) as eluent. This gave 3.29 g (84%) of the title compound as a colorless oil. HRMS m/z calcd for C12H11ClN2O (M)+ 234.0560, found 234.0551.
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:8][C:7]([CH3:10])([CH3:9])[N:6]=[C:5](SC)[N:4]=1.[CH2:13]([OH:15])[CH3:14]>>[NH2:2][C:3]1[NH:8][C:7]([CH3:10])([CH3:9])[N:6]=[C:5]([O:15][CH2:13][CH3:14])[N:4]=1
Reactant: CCO
Reactant: CSC1=NC(C)(C)NC(N)=N1
Agent: [Na]
Product: CCOC1=NC(C)(C)NC(N)=N1

Procedure:
To a solution of sodium (2.3 g., 0.1 gr. atom) in absolute ethanol (100 ml.) is added 2-amino-3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazine (3.4 g., 0.02 mole) and the mixture is heated at reflux for 18 hours. The ethanol is distilled at reduced pressure and the residue dissolved in water (100 ml.) and extracted with ethyl acetate (3×100 ml.) dried over potassium carbonate and evaporated in vacuo to give 1.3 g of 2-amino-3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazine which melts at 175°-8° C. after crystallization from acetonitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCc1ccc(OCc2ccccc2)cc1
Temperature: 56.5 °C
Yield: 77.5 %

Procedure:
Acetone (500 ml) and potassium carbonate (154 g) were charged into RB flask followed by addition of p-hydroxy phenyl acetonitrile (100 g) under stirring. Benzyl bromide (154 g) was then added at ambient temperature, subsequently heating the reaction mass to 55-58° C. and maintaining for 2 hours. The reaction mass was then cooled to 25° C., filtered and washed with acetone (100 ml) to give 130 g (77.8%) of the p-benzyloxyphenyl acetonitrile.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[NH2:23][C@@H:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][C@H:25]1[OH:33].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16]([NH:23][C@@H:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:26][C@H:25]5[OH:33])[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cncnc43)cc2s1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cncnc43)cc2s1
Temperature: 150 °C
Yield: 21.4 %

Procedure:
To a mixture of 6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (270 mg, 0.8 mmol) from Step 2 of the this Example and (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (246 mg, 1.6 mmol) in NMP (1.5 mL) was added DIEA (570 μL, 3.3 mmol). The reaction vessel was sealed and the mixture was heated at 150° C. in the Biotage microwave reactor for 1.5 h. The mixture was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-1-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (71 mg, 21%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 7.11-7.25 (m, 4H), 5.45-5.57 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.28 (m, 1H), 3.16 (dd, J=6.9, 15.5 Hz, 1H), 2.74 (m, 1H). LCMS (ESI) m/z 415 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:35])[C:18]([N:20]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:36][CH3:37].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:35])[C:18]([N:20]([C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.1 g of 3b in 30 ml of dioxane and a solution of 1.5 g of KOH in 10 ml of water were mixed and stirred for 3 hr at RT. 75 ml of water was added and the mixture was acidified with 0.5N HCl to pH3. The product was extracted with ethyl acetate. The material 3c which remained after washing, drying and concentration was used, as such, in the cyclization step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].COC1C=C(OC)C=C2C=1C(=O)N[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]S(C)(=O)=O)[CH2:35][CH2:34]3)[N:28]=1)=N2.[C:46]1(C)C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH2:34][CH2:35][N:36]([CH:39]([CH3:40])[CH3:46])[CH2:37][CH2:38]3)[N:28]=1)=[N:1]2
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CCS(C)(=O)=O)CC4)n3)nc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCN(c2cccc(-c3nc4cc(F)cc(F)c4c(=O)[nH]3)n2)CC1
Temperature: 110 °C
Yield: 20.5 %

Procedure:
A mixture of 2-amino-4,6-difluorobenzamide (7, 330 mg, 1.70 mmol), 6-(4-isopropylpiperazin-1-yl)picolinaldehyde (8, Scheme 6, 330 mg, 1.42 mmol), p-toluenesulfonic acid (590 mg, 3.12 mmol), NaHSO3 (370 mg, 3.55 mmol) and DMA (15 mL) was heated for 24 h at 110° C. under nitrogen. The mixture was partitioned between water (25 mL) and CH2Cl2 (25 mL) and shaken vigorously. The layers were separated and the organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-5% MeOH in CH2Cl2 to provide the title compound (112 mg, 20%): 1H NMR (500 MHz, CDCl3) δ 10.59 (s, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.67 (dd, J=7.3, 8.5 Hz, 1H), 7.30-7.26 (m, 1H), 6.93-6.89 (m, 1H), 6.86 (d, J=8.5 Hz, 1H), 3.69-3.60 (m, 4H), 2.82-2.73 (m, 1H), 2.71-2.66 (m, 4H), 1.12 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]1[C:22]([O:24][CH3:25])=[O:23].[BH4-].[Na+].Cl>CO>[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flask, methanol (1.425 mL) and triethylamine (0.0277 g, 0.274 mmol) was added to 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (0.0587 g, 0.228 mmol). The reaction was allowed to stir at room temperature for 15 minutes. Sodium borohydride (0.0285 g, 0.753 mmol) was added to the flask one portion. The reaction was allowed to stir at room temperature for an additional hour. Using 1N hydrochloric acid, the reaction was neutralized to pH 7 and then concentrated under vacuo. Water (2 mL) was used to dissolve the residue. The mixture was extracted using dichloromethane (3×2 mL). The extracts were combined, washed with saturated sodium bicarbonate, dried using sodium sulfate, and concentrated under vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>CC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15][CH2:14][N:13]([C:29]([O:30][CH2:31][CH3:32])=[O:33])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)c2ccc(F)cc2)(c2ccccc2)CC1
Reaction time: 5 h

Procedure:
To a stirred mixture of 79 parts of (4-fluorophenyl) [4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanone and 630 parts of methylbenzene were added dropwise 32 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued for 5 hours at reflux temperature. The reaction mixture was evaporated and the (chloromethyl)benzene was distilled in vacuo (pump). The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and a small amount of petroleumether, yielding 35.5 parts of ethyl 4-(4-fluorobenzoyl)-4-phenyl-1-piperidinecarboxylate; mp. 91.7° C. (intermediate 15).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[OH-].[K+].[I:15]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[C:6]([I:15])=[N:7][NH:8][C:9]=2[CH:10]=1
Reactant: II
Reactant: N#Cc1cc(Cl)cc2[nH]ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc2[nH]nc(I)c12
Temperature: 50 °C
Yield: 58.8 %

Procedure:
To a solution of 6-chloro-1H-indazole-4-carbonitrile (2.0 g, 11.26 mmol) in DMF (30 mL) was added KOH (1.89 g, 33.78 mmol) and I2 (5.72 g, 22.52 mmol). The mixture was heated at 50° C. overnight. The reaction mixture was quenched with EtOAc (200 mL) and water (100 mL). The organic layer was concentrated in vacuo to afford 6-chloro-3-iodo-1H-indazole-4-carbonitrile as white solid (2.01 g, 58.8%). MS (ESI): m/z=304 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10]C)=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13].P(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: COc1cc(C=O)cc(C=O)c1O
Agent: BrP(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(C=O)c1
Temperature: 0 °C

Procedure:
To a suspension containing 1.8 g of 4-hydroxy-5-methoxyisophtalaldehyde in 20 ml of dichloromethane was added 35 ml of 1 molar PBr3 in dichloromethane. The mixture was allowed to stand over night at room temperature and poured the to ice-water. Dichloromethane was evaporated in vacuo. After cooling the product was filtered and washed with water. Yield 0.94 g (57%), m.p. 192°-195° C.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]([OH:14])=[N:5]1)(=O)C.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:15][O:14][C:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][NH:4][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn(C(C)=O)nc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]nc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.1 g, 10.6 mmol) and potassium carbonate (1.5 g, 10.6 mmol) in 45 mL of DMF is stirred at RT for 30 minutes. Dimethyl sulfate (1.0 mL, 10.6 mmol) in 25 mL of DMF is then added dropwise over 10 min, and the resulting reaction mixture is heated to 70° C. for 4 h. The solvent is evaporated in vacuo, and the residue is dissolved in water and extracted with CH2Cl2 (2×30 mL). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a yellow/brown oil. Purification by silica gel column chromatography (gradient from 50% EtOAc/hexane to 80% EtOAc/hexane) affords the title compound as a clear, viscous oil which slowly solidifies on standing.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:15]2[C:10]3=[C:11]([C:22]4[CH:23]=[C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:25]=[CH:26][C:27]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=2.C1C(=O)N([Br:42])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:42][C:5]1[CH:6]=[CH:7][C:8]2[N:9]3[C:27]4[CH:26]=[CH:25][C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][C:22]=4[C:11]4[CH:12]=[C:13]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:14]=[C:15]([C:2]([CH3:34])([CH3:1])[C:3]=2[CH:4]=1)[C:10]3=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC1(C)c2cc(Br)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Reaction time: 4 h

Procedure:
9.6 g (22.2 mmol) of 8,8-dimethyl-3,6-diphenyl-8H-indolo[3,2,1-de]acridine are initially introduced in 150 ml of CH2Cl2. A solution of 3.9 g (22.3 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane, and the solid is isolated.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:12]([CH:14]([CH3:18])[C:15](O)=O)#[N:13].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][CH2:15][CH:14]([C:12]#[N:13])[CH3:18])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C#N)C(=O)O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C#N)CN[C@@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of alanine tert-butyl ester hydrochloride (41.5 g, 228 mmol) in anhydrous dimethyl formamide (DMF, 35 mL) under argon was added triethylamine (35 mL) followed by 2-cyanopropionic acid (25 g, 252 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 40.5 g, 300 mmol). The resulting mixture was cooled to 0° C. and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 48.8 g, 255 mmol) was added. The mixture was stirred at 0° C. for 2 h followed by 12 h at 23° C. The solvent was removed in vacuo, and the resulting residue was suspended in 300 mL of ethyl acetate. The organic layer was extracted with saturated aqueous NaHSO4 and the precipitate that formed from the emulsion was filtered out. The organic layer was again extracted with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over anhydrous MgSO4 and concentrated to a viscous yellow oil. 1H NMR (CDCl3): δ 1.4 (dd, 3H, CH3—CH—NH—), 1.5 (s, 9H, (CH3)3), 1.6 (dd, 3H, CH3—CH—CN—), 3.5 (q, 1H, NH—CH—CO2Bu), 4.4 (m, 1H, CH3—CH—CN), 6.8 (s, 1H, NH).
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Cl:17].[CH3:18]O>>[NH2:6][C:7]1[C:8]([Cl:17])=[CH:9][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:14][C:15]=1[Cl:16]
Reactant: Nc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
conc. H2SO4 (2.5 mL, 97.04 mmol) was added drop wise to a stirred solution of 4-amino-3,5-dichlorobenzoic acid (10.0 g, 48.54 mmol) in MeOH (150 mL) at 0° C. and the reaction mixture was then stirred at 80° C. for 8 h. The volatiles were evaporated; ice-water was added to the residue and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a white solid (7.5 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 2H), 3.96 (s, 3H); ESIMS m/z 282 ([M]+); IR (KBr): 1733, 762, 514 cm−1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1>ClC(Cl)C.ClCCl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[Br:1][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58.4 %

Procedure:
N-Bromosuccinimide (58.62 g, 329.34 mmol) was added in portions over a period of 5-10 min to a well stirred solution of 4-methyl-2-methoxy-1-nitro benzene (50.0 g, 299.4 mmol) and 1,1′-Azobis(cyclohexane carbonitrile) (1.0 g, 4.1 mmol) in dichloroethane (600 mL) and the resulting mixture was heated to reflux under a UV light for a maximum 7-8 hr. After cooling to rt, the reaction mixture was diluted with dichloromethane (400 mL) and washed with aqueous Na2S2O4 solution, water and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid (102.0 g) which was triturated with diisopropyl ether to afford 43.0 g of the desired product. The diisopropyl ether filtrate was concentrated and purified by silica-gel column chromatography (5-40% EtOAc/Hexanes) to obtain an additional 5.5 g of the desired product (48.5 g, 66%). 1H NMR (CDCl3-300 MHz): δ=3.98 (s, 3H), 4.46 (s, 2H), 7.05 (dd, J=6.60 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:20])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][CH2:18][OH:19])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[N:35]2[CH:36]=[C:37]([O:40][C@H:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C@@H:44]([NH2:51])[CH2:43][CH2:42]3)[CH:38]=[CH:39][C:34]2=[N:33][N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:51][C@@H:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@H:41]([O:40][C:37]3[CH:38]=[CH:39][C:34]4[N:35]([C:31]([C:25]5[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=5[Cl:30])=[N:32][N:33]=4)[CH:36]=3)[CH2:42][CH2:43]2)=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][OH:19])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCCO)n1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5c(Cl)cccc5Cl)n4c3)c3ccccc32)n(CCCO)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A mixture of Intermediate 35b (200 mg, 0.54 mmol), Intermediate 26d (228 mg, 0.54 mmol), and DIPEA (140 μL, 0.80 mmol) in dioxane (2 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to RT, diluted with DCM (10 mL), and washed with water (2×10 mL). The aqueous layer was extracted with DCM, and the combined organics were passed through a phase separator and concentrated in vacuo and the resultant residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM to afford the title compound (270 mg, 76%). A 50 mg sample of this was purified by MDAP (Method 7) to afford the title compound as a glassy solid (17 mg). LCMS (Method 5): Rt 4.24 min, m/z 648.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.79-1.87 (2H, m), 1.88-2.14 (4H, m), 3.41 (2H, t, J=5.9 Hz), 3.91 (2H, t, J=7.2 Hz), 4.58 (1H, br s), 4.79-4.87 (1H, m), 5.55 (1H, t, J=4.2 Hz), 6.03 (1H, s), 6.93 (1H, d, J=8.8 Hz), 7.23-7.29 (1H, m), 7.32-7.38 (4H, m), 7.69-7.79 (3H, m), 7.91 (1H, dd, J=9.6 Hz, 0.9 Hz), 7.98 (1H, d, J=1.7 Hz), 8.17 (1H, s).
Reaction SMILES: C1(N2CC[O:10]CC2)CCCCC=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[C:30]1(C)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C:30]1=[O:10])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccccc1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1CCCCC1C(=O)c1ccccc1
Yield: 50 %

Procedure:
Compound IVc is obtained in 50% yield as a yellow powder, according to Example 4, from 4-cyclohex-1-enyl-morpholine (40.96 g, 0.25 mol, obtained in Example 1), triethylamine (35.35 g, 0.35 mol), benzoyl chloride (49.19 g, 0.35 mol), toluene (380 mL) and 20% aqueous HCl (125 mL).
Reaction SMILES: [CH2:1]([NH:8]CCC1C2C(=CC=C(F)C=2OC)N(C)C=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:26]1[C:34]2[C:29](=[C:30]([O:36][CH3:37])[CH:31]=[CH:32][C:33]=2[F:35])[C:28]([CH2:38][CH2:39]O)=[CH:27]1)[CH3:25]>>[CH2:1]([NH:8][CH2:39][CH2:38][C:28]1[C:29]2[C:34](=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[O:36][CH3:37])[N:26]([CH2:24][CH3:25])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Reactant: CCn1cc(CCO)c2c(OC)ccc(F)c21
Product: CCn1cc(CCNCc2ccccc2)c2c(OC)ccc(F)c21
Yield: 68 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 20-3 was used as starting material, giving compound 20-4 in 68% yield as a white solid, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 9.25 (br, 2H), 7.54-7.57 (m, 2H), 7.42-7.44 (m, 3H), 7.16 (s, 1H), 6.82 (dd, J=12.4, 8.5 Hz, 1H), 6.35 (dd, J=8.5, 2.7 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.17 (s, 2H), 3.75 (s, 3H), 3.12 (br, 4H), 1.32 (t, J=7.1 Hz, 3H). LRMS: calc 326.2 found 327.2 [MH]+.