Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].Cl[Sn]Cl>CO>[NH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)Nc1c(OC)cccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Product: CCOC(=O)Nc1c(N)cccc1OC

Procedure:
25.0 g (0.104 mol) ethyl (2-methoxy-6-nitro-phenyl)-carbamate are dissolved in 400 mL methanol. 116.4 g (0.516 mol) SnCl2 2H2O are added and the mixture is refluxed for 3 hours. The reaction mixture is evaporated down, combined with sodium carbonate solution and filtered. The aqueous phase is repeatedly extracted with dichloromethane and the combined organic phases are washed with sodium chloride solution, dried and evaporated down. The residue that crystallises out on standing is stirred with isopropanol. Yield: 13.0 g (59%); mass spectroscopy: [M+H]+=211.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.[OH-].[Na+]>O>[O:20]1[CH:18]([CH2:16][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:19]1
Reactant: ClCC1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 100 g (506.9 millimoles) of dibenzylamine (dissolved in 300 ml of methylene chloride) is added dropwise to a thoroughly stirred suspension of 234.51 g (2.53 mol) of epichlorohydrin and 200 ml of 32% sodium hydroxide solution. The mixture is stirred for 2 hours at 0° C. and then 3 hours at room temperature. The mixture is diluted with 3 l of water and extracted 3 times with 500 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, and evaporated under vacuum. The remaining oil is flash-chromatographed on silica gel (mobile phase: methylene chloride/hexane/acetone: 20/10/3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19](O)=[O:20])[N:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:9]2=[O:29])=[O:5])[CH3:2].C(OC(C1C(C)=[C:38]2C(=CC=1C)N=C(CCC(OCC)=O)[N:40](C1C=CC=CC=1Cl)[C:39]2=O)=O)C>C(O)C.[OH-].[Na+]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19](=[O:20])[NH:40][CH2:39][CH3:38])[N:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:9]2=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc2nc(CCC(=O)O)n(-c3ccccc3Cl)c(=O)c2c1C
Reactant: CCOC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-(2-Carboxyethyl)-3-(2-chlorophenyl)-5,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-carboxylic acid ethyl ester: A solution of 3-(2-chlorophenyl)-2-(2-ethoxycarbonylethyl)-5,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-carboxylic acid ethyl ester (0.1 g, 0.22 mmol) in absolute ethanol (6 mL) is treated with 2M sodium hydroxide solution (12 drops) and the reaction mixture is stirred at room temperature for 4 days. The solvent is removed under reduced pressure, and the residue is dissolved in water and washed with ethyl acetate. The aqueous layer is acidified to pH2 with concentrated hydrochloric acid and this is extracted with ethyl acetate. The organic phases are combined, dried over anhydrous MgSO4 and the solvent is removed under reduced pressure to afford the title compound, which is used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1)[NH2:16]
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Reactant: NN
Product: NNc1ccc(-c2cccc(Cl)c2)nn1

Procedure:
A slurry of 3-chloro-6-(meta-chlorophenyl)pyridazine (10.25 g.) in anhydrous hydrazine (36 ml) was heated at 82° C. for 3 hours. Upon cooling a solid separated. The solid was isolated by filtration and recrystallized from ethanol to give 3-hydrazino-6-(meta-chlorophenyl)pyridazine, m.p. 173°-174°. When 3-hydrazino-6-(meta-chlorophenyl)-pyridazine was reacted with acrylonitrile using the same procedure described in Example 1, 1-[6'-(meta-chlorophenyl)-pyridazin-3'-yl]-3-aminopyrazol-2-ene was obtained, m.p. 196°-197° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][OH:13])=[N:10][CH:11]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:15])=[O:13])=[N:10][CH:11]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1ccc(OCCCCl)cn1
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OCCCCl)cn1

Procedure:
The mixture of 30.0 g of 5-(3-chloropropoxy)-2-pyridine methanol and 1,200 ml of water is stirred vigorously at 5°. To this mixture is added 31.0 of potassium permanganate in several portions during which time the temperature of the mixture rises to 25° and then the mixture is stirred at 25° for 30 minutes. Then the mixture is filtered, the precipitated manganese dioxide washed with several portions of water, the washing is combined with the filtrate and the resulting aqueous solution is adjusted to pH 5. Then the aqueous solution is evaporated to a small volume and the concentrate is extracted several times with ethyl acetate. After the extracts are combined, the combined ethyl acetate solution is washed and dried. The solution is filtered and the filtrate evaporated to yield 5-(3-chloropropoxy)-2-pyridinecarboxylic acid melting at 120°-121°.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1>C(#N)C>[CH2:6]([N:5]([CH3:4])[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1)[CH:7]=[CH2:8]
Reactant: ClCCNc1ccnc2cc(Cl)ccc12
Agent: Cl
Solvent: CC#N
Product: C=CCN(C)CCNc1ccnc2cc(Cl)ccc12

Procedure:
0.56 g from 2.5 g of N-(2-chloroethyl)-7-chloro-4-quinolinamine hydrochloride; colourless crystals from acetonitrile, m.p.: 91°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[NH:19]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]([NH2:22])=[NH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:21]=[C:20]([NH:19][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:22]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)NCCCC(=O)O
Product: O=C(O)CCCNc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 4-guanidino butyric acid were converted to I-19 (6%): HRMS Calcd. for C16H11ClN4O3: 347.091, Found 347.092.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[CH:21]=[CH2:22].[C:23](=O)([O-])[O-].[K+].[K+].CO.COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CCOCC>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:23])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[CH:21]=[CH2:22]
Reactant: O=C([O-])[O-]
Reactant: C=Cc1c(C(=O)OC)nc(-c2ccc(C=O)cc2)c(F)c1N
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(C=C)c(N)c2F)cc1
Reaction time: 4 h
Yield: 61.8 %

Procedure:
To a 20 mL reaction vial was added methyl 4-amino-5-fluoro-6-(4-formylphenyl)-3-vinylpicolinate (0.41 g, 1.365 mmol), potassium carbonate (0.377 g, 2.73 mmol) and MeOH (10 mL). Dimethyl(1-diazo-2-oxopropyl)phosphonate (0.315 g, 1.638 mmol) was added in one portion. After stirring for 4 h, the reaction mixture was diluted with Et2O (50 mL) and washed with a 5% solution of NaHCO3 (25 mL) The organic layer was dried over MgSO4 (5 g), filtered, and concentrated on a rotary evaporator. The resulting reside was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a white solid (250 mg).
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:11]([CH2:12]O)=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:16]>CC#N>[CH2:1]([S:5][C:6]1[C:11]([CH2:12][Cl:16])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCSc1ncccc1CO
Solvent: CC#N
Product: CCCCSc1ncccc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(2-Butylsulfanyl-pyridin-3-yl)-methanol (0.85 g, 4.3 mmol) obtained in Step B was dissolved in CH3CN (20 mL). SOCl2(0.63 mL, 8.6 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to remove the solvent and then added with EtOAc. The organic layer was washed with water, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.77 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)=[C:4]([O:17][CH3:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH3:18])[C:5]([CH:10]2[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cc(Cl)cc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(4-chloro-2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.84 min.; [M+H]+: 444.09 g/mol.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC3CCCCC3)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](CNc2nc(NCC3CCCCC3)ncc2[N+](=O)[O-])CC1
Yield: 35.5 %

Procedure:
The above (4-{[2-(cyclohexylmethylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (32 mg, 0.07 mmol) was dissolved in dioxane (0.6 mL) and treated with 4M HCl in dioxane (0.25 mL). The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel preparative TLC to afford 9 mg (35%) of the title compound, m/z 363.4 [M+1]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]2[CH:9]=[CH:10][CH2:11][O:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:6]>CO.O>[O:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:7]([C:5]([OH:6])=[O:4])[C:8]=2[CH:9]=[CH:10][CH2:11]1
Reactant: COC(=O)c1cccc2c1C=CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c1C=CCO2
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A solution of NaOH (7.26 mmol) in a mixture of MeOH (5.4 mL) and water (12.1 mL) is added to 2H-chromene-5-carboxylic acid methyl ester (4.84 mmol). The mixture is stirred at 55° C. for 3 h, partially concentrated in vacuo to remove MeOH and made acidic by addition of hydrochloric acid (1.0M). The desired carboxylic acid precipitates and is collected by filtration. 1H-NMR (DMSO-d6): δ=4.75 (bs, 2H); 5.99-6.05 (m, 1H); 6.98 (d, J=7.78 Hz, 1H); 7.19 (t, J=7.78 Hz, 1H); 7.25 (d, J=10.3 Hz, 1H); 7.40 (d, J=7.78 Hz, 1H); 13.0 (bs, 1H).
Reaction SMILES: COC1C=C(N2CCC(N3CCN(C)CC3)CC2)C=CC=1N.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:33]1[N:38]=[C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([N:52]4[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]4)[CH2:48][CH2:47]3)=[CH:42][C:41]=2[O:59][CH3:60])[C:36]([Cl:61])=[CH:35][N:34]=1.[CH3:62][P:63]([C:66]1[N:67]=[C:68]([O:73][CH3:74])[C:69]([NH2:72])=[N:70][CH:71]=1)([CH3:65])=[O:64]>>[Cl:61][C:36]1[C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([N:52]4[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]4)[CH2:48][CH2:47]3)=[CH:42][C:41]=2[O:59][CH3:60])=[N:38][C:33]([NH:72][C:69]2[C:68]([O:73][CH3:74])=[N:67][C:66]([P:63]([CH3:62])([CH3:65])=[O:64])=[CH:71][N:70]=2)=[N:34][CH:35]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1nc(P(C)(C)=O)cnc1N
Agent: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1nc(Nc2ncc(P(C)(C)=O)nc2OC)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine. 2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine is then reacted with 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in Example 33) according to the procedure described in Example 32.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:32](=[O:34])[CH3:33])=[CH:26][C:25]=1[CH3:35].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.N#N>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:24]4[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:32](=[O:34])[CH3:33])=[CH:26][C:25]=4[CH3:35])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Nc1cc(C)c(Br)c(C)c1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C)c(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)c(C)c1
Temperature: 130 °C
Reaction time: 13.5 h
Yield: 41.1 %

Procedure:
A mixture of 2-cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100.0 mg, 0.307 mmol), N-(4-bromo-3,5-dimethyl-phenyl)-acetamide (112. mg, 0.461 mmol), palladium(II) acetate (10 mg, 0.0461 mmol), tris(o-tolyl)phosphine (28 mg, 0.0922 mmol), triethylamine (0.128 ml, 0.922 mmol) and DMA (1.5 ml) was added to a sealed test tube in an N2 atmosphere. This mixture was heated with stirring at 130° C. for 13.5 hours. Palladium(II) acetate (10 mg, 0.0461 mmol), tris(o-tolyl)phosphine (28 mg, 0.0922 mmol) and triethylamine (0.128 ml, 0.922 mmol) were further added to the reaction mixture at room temperature in an N2 atmosphere, and the mixture was heated with stirring at 130° C. for 14 hours. The reaction mixture was cooled and water was then added. The aqueous layer was extracted with ethyl acetate (×3). The organic layers were combined and sequentially washed with water (×2) and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CH2Cl2-MeOH) to give N-{4-[(E)-2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-vinyl]-3,5-dimethyl-phenyl}-acetamide (61.4 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23](C#N)[CH:22]=[C:21]([Cl:27])[C:3]=1[C:4]([N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)=[O:5].N1C2C=C(N(C(C)(CC(C)(C)C)C)C(C3CC3)=O)N=CC=2C=C1.C(C1C=C(Cl)C(C(Cl)=O)=C(Cl)C=1)#N>>[Cl:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[C:3]=1[C:4]([N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]([CH:18]3[CH2:19][CH2:20]3)=[O:17])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)=[O:5]
Reactant: N#Cc1cc(Cl)c(C(=O)n2ccc3cnc(NC(=O)C4CC4)cc32)c(Cl)c1
Agent: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2[nH]ccc2cn1
Agent: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Product: O=C(Nc1cc2c(ccn2C(=O)c2c(Cl)cccc2Cl)cn1)C1CC1

Procedure:
N-[1-(2,6-dichloro-4-cyanobenzoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]cyclopropane carboxamide (Compound No. 137) was prepared from N-(1H-pyrrolo[3,2-c]pyridin-6-yl)-N-(2,4,4-trimethylpentan-2-yl)cyclopropane carboxamide by treating with 4-cyano-2,6-dichlorobenzoyl chloride following a procedure as per step k and l in Example 27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2cc(Br)cnc2=O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(Br)cnc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-bromo-1-(4-oxo-cyclohexyl)-1H-pyrimidin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: P(OCCOC(N1C2C(=CC=CC=2)/C(=C/C2NC(C)=CC=2C)/C1=O)=O)(O)(O)=O.CO[O:31][P:32]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42]([N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)/[C:46](=[CH:53]/[C:54]2[NH:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])/[C:45]1=[O:61])=[O:43])([O:34]OC)=[O:33]>>[P:32]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42]([N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)/[C:46](=[CH:53]/[C:54]2[NH:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])/[C:45]1=[O:61])=[O:43])([OH:34])([OH:33])=[O:31]
Reactant: COOP(=O)(OCCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Agent: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCOP(=O)(O)O)c3ccccc32)[nH]1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCCOP(=O)(O)O)c3ccccc32)[nH]1

Procedure:
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-phosphonooxy-propyl ester was prepared using the same procedure for preparing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-phosphonooxyethyl ester but substituting 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphonooxy)-ethyl ester with 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)propyl ester.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1)(=[O:5])=[O:4].O1CC[CH2:19]OO1>CS(O)(=O)=O.FC(F)(F)C(O)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:8]2=[C:7]3[C:14]=1[CH2:1][N:2]([CH3:19])[S:3](=[O:4])(=[O:5])[C:6]3=[CH:10][S:9]2
Reactant: CNS(=O)(=O)c1csc2ccc(Cl)cc12
Reactant: C1COOOC1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(Cl)ccc3scc(c23)S1(=O)=O
Temperature: 35 °C
Reaction time: 3 h

Procedure:
0.60 g of 5-chloro-benzo[b]thiophene-3-sulphonic acid-methylamide are dissolved in 8.9 ml of methanesulphonic acid at 35° C. and combined with a solution of 0.09 g trioxane in 2.7 ml trifluoroacetic acid. After 3 h stirring at 35° C. the reaction mixture is poured onto 100 ml of ice water and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried with Na2SO4, evaporated down in vacuo and then purified by chromatography. Yield: 0.30 g. M.p.: 196° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.[C:17](=[NH:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:17](=[N:30][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(=O)N1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=O)N1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one (building block B) (1.2 g, 4.17 mmol) in toluene (20 ml) was treated with benzophenonimine (1.59 g, 8.33 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (133 mg, 0.125 mmol), tert-butyl X-phos (182 mg, 0.417 mmol) and sodium tert-butoxide (1.24 g, 12.5 mmol). The mixture was stirred in a sealed tube at 105° C. for 18 hours. For the workup, the brown reaction mixture was evaporated and the residue directly purified by flash chromatography on a silica-amine phase using a gradient of heptane/ethyl acetate=100:0 to 40:60 as the eluent. The (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one was obtained as a yellow solid (1.53 g, 95%); (calculated) C24H21FN2O2 [388.45]; (found) [M+H]+=389.
Reaction SMILES: C(=O)[CH2:2][CH2:3][CH:4]=[O:5].N1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].COC(C)(C)C>C1COCC1>[OH:10][CH:9]1[O:11][C@H:13]2[CH2:14][C:3]([CH:4]=[O:5])=[CH:2][C@H:12]2[CH2:8]1
Reactant: O=CCCC=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The solution of succinaldehyde 8 (57.5 g, 668 mmol) in THF (334 ml) obtained in Example 1B was stirred at r.t. (S)-Proline (1.54 g, 13.4 mmol, 0.02 eq.) was added as a solid and the reaction stirred at r.t. for 20 h. THF (334 ml) was added, followed by [Bn2NH2][OCOCF3] (4.16 g, 13.4 mmol, 0.02 eq.). The reaction was stirred for a further 14 h. The volume of the reaction mixture was reduced by half under reduced pressure. tert-Butyl methyl ether (TBME) (334 ml) was added and the mixture stirred for 20 min before filtration of the resulting solids (through a sinter funnel). The solids were washed with TBME (3×50 ml) and the filtrate was concentrated under reduced pressure. (Note: During concentration of the filtrate, for the purposes of this example it is important not to heat the water bath of the rotary evaporator). The material was purified by column chromatography (˜350 g silica), eluting with petrol/EtOAc (6:4 to 4:6), to give the lactol 7 (as an approximately 2:1 mixture of diastereoisomers, 16%), as a brown oil. This material is of sufficient purity to take forward for the next transformation (see Example 3C). While it does contain some unreacted succinaldehyde and oligomeric side-products these do not interfere with the subsequent transformation and purification.